review article
Pharmacokinetic drug‑drug interaction and their
implication in clinical management
Palleria Caterina, Di Paolo Antonello1, Giofrè Chiara, Caglioti Chiara, Leuzzi Giacomo2, Siniscalchi Antonio3,
De Sarro Giovambattista, Gallelli Luca
Department of Health Science, School of Medicine, University of Catanzaro, Rete Regionale di Informazione Sul Farmaco,
AO MaterDomini Catanzaro, 1Department of Clinical and Experimental Medicine, Division of Pharmacology, University of Pisa,
2
Azienda Sanitaria Provinciale Catanzaro, Department of Primary Care, 3Department of Neurology, Cosenza Hospital, Italy
Drug‑drug interactions (DDIs) are one of the commonest causes of medication error in developed countries, particularly in the elderly
due to poly‑therapy, with a prevalence of 20‑40%. In particular, poly‑therapy increases the complexity of therapeutic management
and thereby the risk of clinically important DDIs, which can both induce the development of adverse drug reactions or reduce the
clinical eicacy. DDIs can be classify into two main groups: pharmacokinetic and pharmacodynamic. In this review, using Medline,
PubMed, Embase, Cochrane library and Reference lists we searched articles published until June 30 2012, and we described the
mechanism of pharmacokinetic DDIs focusing the interest on their clinical implications.
Key words: Absorption, adverse drug reaction, distribution, drug‑drug interactions, excretion, metabolism, poly‑therapy
How to cite this article: Caterina P, Antonello DP, Chiara G, Chiara C, Giacomo L, Antonio S, et al. Pharmacokinetic drug‑drug interaction and their
implication in clinical management. J Res Med Sci 2013;18:600‑609.
INTRODUCTION
Pharmacovigilance or post‑marketing surveillance aims
to identify and quantify the risks associated with the
use of drugs, thus contributing to beter understand
the most important characteristics of adverse drug
reactions (ADRs) and the pathogenic mechanisms
involved.[1] Indeed, ADRs represent a common clinical
problem and can be responsible for an increased number
and/or duration of hospitalizations.[2,3]
Drug‑drug interactions (DDIs) are one of the
commonest causes of ADRs and we reported that
these manifestations are commons in the elderly due
to poly‑therapy.[4‑7] In fact, poly‑therapy increases the
complexity of therapeutic management and thereby the
risk of clinically relevant drug interactions, which can
induce the development of ADRs, and both reduce,[8,9]
or increase the clinical eicacy.[10,11]
Poly‑therapy may determine the “prescribing cascade,”
which occurs when an ADR is misunderstood and
new potentially unnecessary drugs are administered;
therefore the patient is at risk to develop further ADRs.[12]
DDI can be classify into two main groups:
• Pharmacokinetic: Involves absorption, distribution,
metabolism and excretion, all of them being
associated with both treatment failure or toxicity;
• Pharmacodynamic: may be divided into
three subgroups: (1) direct effect at receptor
function, (2) interference with a biological or
physiological control process and (3) additive/
opposed pharmacological efect.
In this review, we described the mechanism of
pharmacokinetic DDI focusing the interest on their
clinical implications, addressing the reader’s atention
for pharmaceutical interactions to other original and
review articles.
METHODS
Medline, PubMed, Embase, Cochrane library and
Reference lists were searched for articles published
until June 30 2012, using the words “ADR,” “drug
interactions,” “polytherapy,” “elderly.”
Pharmacokinetic DDI
Pharmacokinetic interactions are oten considered on
the basis of knowledge of each drug and are identiied
by controlling the patient’s clinical manifestations as
well as the changes in serum drug concentrations. As
above reported, they involved all the processes from
absorption up to excretion that will be now described.
Address for correspondence: Dr. Gallelli Luca, Department of Health Science, School of Medicine, University of Catanzaro, Viale Europa
Germaneto 88100, Catanzaro, Italy. E‑mail: gallelli@unicz.it
Received: 21‑08‑2012; Revised: 15‑12‑2012; Accepted: 14‑01‑2013
| July 2013 |
Journal of Research in Medical Sciences
600
Caterina, et al.: Pharmacokinetic drug‑drug interaction
Absorption
Gastro‑intestinal absorption
The complexity of the gastro‑intestinal tract, and the efects
of several drugs with functional activity on the digestive
system, represent favourable conditions for the emergence
of DDI that may alter the drug bioavailability.[13]
Several factors may inluence the absorption of a drug
through the gastrointestinal mucosa. The irst factor is
the change in gastric pH. The majority of drugs orally
administered requires, to be dissolved and absorbed, a
gastric pH between 2.5 and 3. Therefore, drugs able to
increase gastric pH (i.e., antacids, anticholinergics, proton
pump inhibitors [PPI] or H2‑antagonists) can change the
kinetics of other co‑administered drugs.
In fact, H2 antagonists (e.g., ranitidine),
antacids (e.g., aluminium hydroxide and sodium
bicarbonate) and PPI (e.g., omeprazole, esomeprazole,
pantoprazole) that increase the gastric pH lead to a decrease
in cefpodoxime bioavailability, but on the other hand,
facilitate the absorption of beta‑blockers and tolbutamide.
Moreover, antifungal agents (e.g., ketoconazole or
itraconazole), requires an acidic environment for being
properly dissolved, therefore, their co‑administration with
drugs able to increase gastric pH, may cause a decrease
in both dissolution and absorption of antifungal drugs.[14]
Therefore, antacid or anticholinergics, or PPI might be
administered at least 2 h after the administration of
antifungal agents.[15]
Similarly, the administration of drugs able to increase
the gastric pH (see above) with ampicillin, atazanavir,
clopidogrel, diazepam, methotrexate, vitamin B12,
paroxetine and raltegravir are not recommended.
In contrast, the ingestion of drugs that cause a decrease in
gastric pH (e.g., pentagastrin), may have an opposite efect.
It is worth noting that severity of DDIs caused by alteration
of gastric pH mainly depends on pharmacodynamics
characteristics of the involved drug, in terms of narrow
therapeutic range.
Another factor that modifies the drug absorption
is the formation of complexes. In this case,
tetracyclines (e.g., doxycycline or minocycline) in the
digestive tract can combine with metal ions (e.g., calcium,
magnesium, aluminum, iron) to form complexes poorly
absorbed. Consequently certain drugs (e.g., antacids,
preparations containing magnesium salts, aluminum and
calcium preparations containing iron) can signiicantly reduce
the tetracyclines absorption.[16] Analogously, antacids reduce
the absorption of luoroquinolones (e.g., ciproloxacin),
601
penicillamines and tetracyclines, because the metal ions
form complexes with the drug. In agreement, was observed
that antacids and luoroquinolones should be administered
at least 2 h apart or more.[17,18]
Cholestyramine and colestipol bind bile acids and prevent
their absorption in the digestive tract,[19] but they can also bind
other drugs, especially acidic drugs (e.g., warfarin, acetyl
salicylic acid, sulfonamides, phenytoin, and furosemide).
Therefore, the interval between the administration of
cholestyramine or colestipol and other drugs may be as
long as possible (preferably 4 h).[20]
Motility disorders represent the third factor involved
in absorption DDIs. Drugs able to increase the gastric
transit (e.g., metoclopramide, cisapride or cathartic) can reduce
the time of contact between drug and mucosal area of absorption
inducing a decrease of drug absorption (e.g., controlled‑release
preparations or entero‑protected drugs).[21]
For example, metoclopramide, may accelerate gastric
emptying, hence decreasing the absorption of digoxin and
theophylline whereas it can accelerate the absorption of
alcohol, acetylsalicylic acid, acetaminophen, tetracycline
and levo‑dopa.[22]
Finally, iron can inhibits the absorption of levodopa and
metildopa.
Modulation of P‑glycoprotein (P‑gp) intestinal
P‑gp or gp‑120 for its molecular weight, is a transmembrane
protein encoded by the human multidrug resistance
gene‑1 belonging to the adenosine triphosphate‑binding
cassette (ABC) superfamily, together with other 41
members grouped in 7 families (A to G).[23] Localized in
liver, pancreas, kidney, small and large intestine, adrenal
cortex, testes and leukocytes, P‑gp plays a protective role
influencing the trans membrane drugs diffusion thus
reducing their absorption or increasing their excretion
or limiting their tissues distribution (i.e., central nervous
system, foetal and gonadic tissues).[24]
P‑gp regulates the intestinal absorption of drugs (it is present
on the luminal surface of enterocytes) and promotes their
excretion (it is present on the side tubular of epithelium
renal and biliary side of hepatocytes). Therefore, the
administration of drugs able to stimulate to inhibit the
activity of P‑gp, can induce the development of DDI.
The P‑gp inhibition can significantly increase the
bioavailability of drugs poorly absorbed.[25]
Among the interactions studied at the time of this
review, it is worth mentioning the efects of terfenadine
Journal of Research in Medical Sciences
| July 2013 |
Caterina, et al.: Pharmacokinetic drug‑drug interaction
on the transport of doxorobucin as well as the effects
chlorpromazine and progesterone on the transport
of cyclosporine. [26] The DDIs on P‑gp might induce a
clinical efect in presence of drugs with a low therapeutic
index (e.g., digoxin, theophylline, anticancer drugs) when
co‑administered with macrolides (e.g., erythromycin,
roxithromycin, clarithromycin), PPIs (e.g., omeprazole or
esomeprazole) or anti‑arrhythmic drugs (e.g., dronaderon,
amiodarone, verapamil or diltiazem).
Many drugs (but not all) that are transported by P‑gp
are also metabolized by cytochrome P450 (CYP) isoform
3A4 (e.g., cyclosporine, antiepileptic drugs, antidepressant,
luoroquinolones, quinidine and ranitidine), which can
confound interpretation of interactions (see later).
Therefore, the co‑administration of these drugs with known
inhibitors of P‑gp above described results in a clinically
evident DDI.
Recently, it has been described that aripiprazole and its
active metabolite, dehydroaripiprazole, but no risperidone,
paliperidone, olanzapine and ziprasidone are strong P‑gp
inhibitors, in vitro, while in vivo their administration is
unlikely to induce DDIs at the blood‑brain‑barrier, but the
possibility of DDIs in the intestine cannot be neglected.
However, it is important to underline that a DDI could
be also used in clinical management. In fact, Shi et al.[27]
documented that sildenail inhibits the transporter function
of P‑gp, suggesting a possible strategy to enhance the
distribution and potentially the activity of anticancer drugs.
DISTRIBUTION
Usually, drugs are transported through a binding to
plasma and tissues proteins. Of the many plasma proteins
interacting with drugs, the most important are albumin,
α1‑acid glycoprotein, and lipoproteins. Acidic drugs are
usually bound more extensively to albumin, while basic
drugs are usually bound more extensively to α1‑acid
glycoprotein, lipoproteins, or both. Only unbound drug
is available for passive difusion to extravascular or tissue
sites and typically determines drug concentration at the
active site and thus its eicacy. Albumin represents the
most prominent protein in plasma, it is synthesized in
the liver and distributed in both plasma and extracellular
luids of skin, muscles and various tissues. Intestinal luid
albumin concentration is about 60% of that in the plasma.
Since albumin has ive binding sites (i.e., for warfarin,
benzodiazepines, digoxin, bilirubin and tomoxifen), the
main characterized are the site I and II.[28]
Site I, also known as the warfarin binding site, is formed
| July 2013 |
by a pocket in subdomain IIA,[29] while site II located in
subdomain IIIA is known as the benzodiazepine‑binding
site. Ibuprofen and diazepam are selective drug probes for
site II.[29‑31] [Table 1]
As the free molecules interact with their molecular
targets and are metabolized, other molecules come into
solution to reach the site of action. The degree of plasma
protein binding, expressed by the ratio of bound drug
concentration/free drug concentration, varies greatly
among drugs, possibly reaching very high values, especially
when it is greater than 0.9, otherwise it is considered to be
low (<0.2). Drugs that have a high degree of plasma protein
binding are potentially more likely to be displaced by
drug with greater ainity for the same binding site. From
a mere clinical point of view, that displacement could be
associated with symptoms, side efects or toxicities when
the displaced drug has a higher degree of binding to plasma
proteins (>90%), reduced volume of distribution, narrow
therapeutic index, and it is characterized by a faster onset
of the efect
A typical pharmacological displacement can be observed
when warfarin and diclofenac are co‑administered. Warfarin
and diclofenac have same ainity for albumin, therefore the
administration of diclofenac to a patient treated chronically
with warfarin results in displacement of later from its
binding site. The increase in plasma concentration of free
warfarin causes the development of serious hemorrhagic
reactions.
Metabolism
The CYP enzyme family plays a dominant role in the
biotransformation of a wide number of drugs. In man,
there are about 30 CYP isoforms, which are responsible
for drug metabolism and these belong to families 1‑4,
but only 6 out of 30 isoforms belonging to families CYP1,
2 and 3 (i.e., CYP1A2, 3A4, 2C9, 2C19, 2D6 and 2E1) are
mainly involved in the hepatic drug metabolism.[32‑35]
Table 1: Drugs binding to site I (warfarin) or II
(benzodiazepines) of albumin
Site I (warfarin)
Chlorothiazide
Phenytoin
Glibenclamide
Naproxen
Salicylates
Nimesulide
Diclofenac
Sulphamidics
Fluoroquinolones
Valproate
Journal of Research in Medical Sciences
Site II (benzodiazepines)
Ketoprofen
Ibuprofen
Indomethacin
Dicloxacilline
Nimesulide
602
Caterina, et al.: Pharmacokinetic drug‑drug interaction
The broad range of drugs that undergo CYP mediated
oxidative biotransformation is responsible for the large
number of clinically signiicant drug interactions during
multiple drug therapy. Many DDIs are related to the
inhibition or induction of CYP enzymes.
Similar DDI are seen in the combined administration of
thioridazine and propranolol (CYP2D6), [43] fluoxetine
and desipramine (CYP2D6),[44] omeprazole and diazepam
(CYP2C19),[45‑47] tolbutamide and phenytoin (CYP2C9),[48]
and diltiazem and cyclosporin (CYP3A).[49‑51]
Inhibition
Inhibition‑based DDIs constitute the major proportion of
clinically relevant DDIs. In this process enzyme activity is
reduced due to direct interaction with a drug, usually begins
with the irst dose of the inhibitor, while the extinction of
inhibition is related to the drug half‑lives.[36,37]
Omeprazole, a CYP2C19 inhibitor, decreases the antiplatelet
activity of clopidogrel by inhibiting the biotransformation
of the clopidogrel pro drug into its active metabolite.[52]
In patients hospitalized for acute coronary syndrome,
this interaction is associated with a 27% increased risk
of death or re‑hospitalization.[53] By analogy, inhibition
of CYP2C19 by etravirine may also inhibit clopidogrel
antiplatelet activity. Until more data become available, the
co‑administration of CYP2C19 inhibitors (e.g., etravirine
and omeprazole) and clopidogrel is not recommended.
The metabolic inhibition may be reversible (competitive,
metabolic‑intermediate complex, non‑competitive) or
irreversible, and clinical efects are inluenced by basic
mechanisms.
Reversible inhibition
Competitive
The competitive inhibition occurs when inhibitor and
substrate compete for the same binding site on the enzyme.
In this type of interaction, the inhibition mechanism is direct
and is rapidly reversible.
The drugs are converted through multiple CYP dependent
steps to nitroso‑derivatives that bind with high ainity to
the reduced form of CYP enzymes. Thus CYP enzymes
are unavailable for further oxidation and synthesis of new
enzymes is therefore, the only means by, which activity can
be restored and this may take several days.[38]
It depends on the substrate‑versus‑inhibitor binding
constant ratio, and on the relative concentrations of each
species. Some of the inhibitors of CYP3A4 that act by this
mechanism of inhibition include azole antifungal agents,
some HIV protease inhibitors such as nelinavir mesylate,[39]
and antihypertensives such as diltiazem.[40] In particular, it
has been reported a two‑fold decrease in oral clearance of
metoprolol in presence of propafenone; therefore, during
a co‑administration the dose of metoprolol should be
reduced.[41]
However, recently we reported a case of an 85‑year‑old
woman that developed visual hallucinations and
psychomotor agitation during the treatment with
venlafaxine and propafenone.[42] We postulated a DDI
between venlafaxine and propafenone because venlafaxine
is metabolized primarily by CYP2D6 and is a substrate of
P‑gp, while propafenone is a known substrate and inhibitor
of both CYP2D6 and P‑gp. Therefore, propafenone may be
induced an increase of venlafaxine plasma concentrations
with the development of hallucinations.
603
Moreover, omeprazole treatment should be well evaluated
in elderly patients due the possibility to induce the
development of ADR. In fact, previously we reported in an
elderly man the development of delirium probably related
to a DDI between omeprazole and amitriptyline through
the CYP2C19 inhibition.[54]
Amiodarone is metabolized by CYP3A4 and 2C8; in vitro
is an inhibitor of CYP3A4, 1A2, 2C9 and 2D6. Due to its
long half‑life (about 30 days), the risk of interaction must
be extended also at the period ater the treatment with
amiodarone. However, the risk of interactions may also
depend on its main metabolite, desethylamiodarone, a
competitive inhibitor of CYP2D6, an irreversible inhibitor
of CYP2A6, 3A4, and 2B6 (for formation of covalent bond),
a mixed inhibitor of CYP1A1, 1A2, 2C9 and 2C19.[55]
Similarly, HIV protease inhibitors (i.e., saquinavir and
ritonavir) increase sildenail serum concentrations up to
11‑fold.[56] Similarly, it has been recently reported that
azole antifungal drugs (i.e., ketoconazole, itraconazole,
voriconazole and posaconazole) are CYP3A inhibitors
able to induce DDIs.[57] In particular posaconazole exhibit
inhibitory efects upon CYP3A and PGP and at the dosage
of 200 mg for 10 days can able to reduce from 1.2 to 1.5
fold the steady‑state clearance of cyclosporine. Moreover,
in an open‑label study performed in 36 healthy volunteers,
the treatment with posaconazole (400 mg twice daily) for
14 days increased the plasma concentrations of tacrolimus of
2.2‑fold, the area under the curve (AUC) of 4.5‑fold, and the
half‑life up to 7.5 h.[58] Therefore, the dosage of tacrolimus
should be reduced up to 66% of the original dose, in presence
of posaconazole. Similar DDI have been documented when
azole antifungal treatment was administered in patients
taking sirolimus or everolimus, therefore, an empiric dose
reductions of 50% may be considered for both sirolimus
and everolimus.
Journal of Research in Medical Sciences
| July 2013 |
Caterina, et al.: Pharmacokinetic drug‑drug interaction
However, in a single‑centre study enrolling 20 healthy
subjects, Kapil et al.,[59] documented the lack of a clinically
signiicant CYP3A4 interaction between ketoconazole and
transdermal delivery of buprenorphine. It is consistent
with the parenteral administration of a high clearance
drug bypassing exposure to gut wall and hepatic CYP3A4
irst‑pass efects.
Metabolic‑intermediate complexes
The production of metabolic‑intermediate complexes is
an unusual form of inibition where the inhibitor binds
only to the enzyme‑substrate complex. The formation of a
metabolic‑intermediate complexes results from inhibitors that
have an N‑alkyl substituent. Ater the binding of inhibitor, the
later is oxidized by 3A4 and the resultant oxidized species
of the inhibitor remains complexed with the reduced heme
group of CYP3A4 forming a complex slowly reversible.
Erythromycin is a well‑known CYP3A4 inhibitors that use this
mechanism of inhibition,[60] whereas clarythromycin display
reduced inhibitory efects with a good clinical eicacy.[61]
Non‑competitive
In the non‑competitive mechanism, the inhibitor and
substrate do not compete for the same active site, because
the presence of an allosteric site. Once a ligand binds the
allosteric site the conformation of the active site changes,
its ability to bind the substrate decreases and the product
formation tails off. Many drugs are non‑competitive
inhibitors of CYP isoforms, as well as omeprazole and
lansoprazole, and cimetidine.[62,63] The duration of this type
of inhibition may be longer if new enzymes have to be
synthesized ater the inhibitor drug is discontinued.
Irreversible inhibition
The metabolite resulting from the oxidation of the substrate
by CYP3A4 becomes irreversible and covalently bound
to 3A4, thus leading to a permanent inhibition of the
enzyme. In the case of irreversible inhibition the critical
factor is represented by the total amount rather than the
concentration of the inhibitor to which CYP isoenzyme is
exposed. Lipophilic and large molecular size drugs are more
likely to cause inhibition.[25] Two characteristics make a drug
susceptible to inhibitory interactions: one metabolite must
account for >30‑40% metabolism of a drug and that
metabolic pathway is catalyzed by a single isoenzyme.[48]
Inhibitor will decrease the metabolism of substrate and
generally lead to increased drug efect or toxicity of the
substrate. If the drug is a pro drug the efect is decreased.
Garraffo et al. investigated in an open‑label study the
effects of single‑dose administration and steady‑state
concentrations of tipranavir 500 mg and ritonavir 200 mg
combination on the pharmacokinetics of tadalail 10 mg.[64]
| July 2013 |
The authors documented that even if antiretroviral activity
of both tipranavir and ritonavir may not be reduced,
the dose of tadalafil should be reduced at the start of
antiretroviral therapy and then a full dose can be resumed
ater steady state is reached.
The co‑administration of 3A4 inhibitors with the
hydroxymethylglutaryl‑coenzyme A reductase
inhibitors (statins; e.g., simvastatin) could increase the risk of
myopathy[65] and rhabdomyolysis.[66] However, it is important
to understand that during the treatment with statins it is
possible the development of myopathy also for metabolic
saturation, in particular during the poly‑therapy.[67]
Metabolic induction
Drug interactions involving enzyme induction are not
as common as inhibition‑based drug interactions but
equally profound and clinically important. Exposure to
environmental pollutants as well as the large number of
lipophilic drugs can result in induction of CYP enzymes.
The most common mechanism is transcriptional activation
leading to increased synthesis of more CYP enzyme
proteins.[61] The efect of induction is simply to increase the
amount of P450 present and speed up the oxidation and
clearance of a drug.[43]
The most commons enzyme inducers are rifampicin,[68‑76]
phenobarbital,[76,77] phenytoin,[77,78] carbamazepine,[78‑80] and
anti‑tubercular drugs.[79]
Rifampicin induces CYP3A enzymes in the liver, although
weak induction of other CYP enzymes, including, CYP2A6,
CYP2C and CYP2B6, have also been noticed. Rifampicin
increases the elimination of a large number of drugs,
although most of them are substrates for CYP3A4, such as
midazolam, quinidine, cyclosporine A and many steroids.
Metabolism of the afected drug is increased leading to
decreased intensity and duration of drug efects.[81] It is rather
diicult to predict the time‑course of enzyme induction because
of several factors, including the half‑life and the enzyme
turnover, which determine the time‑course of induction.
A complicating factor is that the time‑course of induction
depends on the time required for enzyme degradation and
new enzyme production.
The short half‑life of rifampicin results in enzyme
induction (CYP3A4, CYP2C), apparent within 24 h, whereas
phenobarbital, which has a half‑life of 3‑5 days, requires
approximately 1 week for induction (CYP3A4, CYP1A2,
CYP2C) to become apparent. These enzyme‑induction
reactions also occur with smoking and long‑term alcohol
or drug consumption and can reduce the duration of action
of a drug by increasing its metabolic elimination.
Journal of Research in Medical Sciences
604
Caterina, et al.: Pharmacokinetic drug‑drug interaction
Recently, we documented in a patient with epilepsy a DDI
between phenobarbital and lamotrigine that induced the
development of leukopenia and thrombocytopenia. We
postulated that CYP enzyme induction by phenobarbital
could be responsible for the production of reactive
metabolites of lamotrigine that might be causative for the
observed hematologic efects.[82]
DDIs during excretion
T h e o r g a n s a n d ve h i c l e s d e p u t y a t t h e d r u g s
excretion (elimination) are kidneys, liver, lungs, feces,
sweat, saliva, milk. The excretion through saliva, sweat and
lungs (for volatile drugs) and milk has litle quantitative
signiicance, but the milk is important when the drugs can
reach the baby during lactation.
Drugs are excreted mainly through:
• Renal tubular excretion (glomerular iltration, tubular
reabsorption and active tubular secretion)
• Biliary excretion.[83]
The drugs elimination from the body can undergo many
interactions being excreted by another drug in this organ
from, which it is excreted.[84]
The kidney is the organ responsible for the elimination of
drugs and their metabolites. The interaction may occur for
a mechanism of competition at the level of active tubular
secretion, where two or more drugs use the same transport
system. An example is given by NSAIDs that determine the
appearance of toxic efects caused by methotrexate when the
renal excretion of the anti‑proliferative drug is blocked.[85]
It was also demonstrated that amoxicillin decreased the
renal clearance of methotrexate.[86]
Probenecid, a potent inhibitor of the anionic pathway of
renal tubular secretion, increases of 2.5 times the area under
the AUC of oseltamivir.[87]
However, this competition between drugs can be exploited
for therapeutic purposes. For example, probenecid can
increase the serum concentration of penicillins and
cephalosporins, delaying their renal excretion and thus
saving in terms of dosage. In fact, probenecid acts by
competitively inhibiting an organic anion transporter
in renal tubules, thus increasing plasma concentrations
of other transporter substrates, while reducing their
excretion.[88]
Several drugs are able to interfere with tubular transport.
In particular, cimetidine, an H2 receptor inhibitor, may
inluence the tubular secretion of diferent molecules. Its
efect on the inlux and the elux of organic cations through
605
human organic cation transporter ([hOCT1 and hOCT2]
and human multidrug and toxin extrusion [hMATE1 and
hMATE2‑K]) could modify other drug serum concentration
despite a normal renal function.[89]
Moreover, in vitro study documented that PPIs
(i.e., omeprazole, pantoprazole, lansoprazole, rabeprazole,
and tenatoprazole) are potent hOCT‑inhibitors and
could modulate the transport of metformin.[90] However,
the clinical relevance of this DDIs may be clarify. The
interactions can also occur during tubular reabsorption.
Many drugs, when they are in an ionized form in the urine,
pass by difusion in tubular cells. The changes in urinary pH,
pharmacologically induced, inluence the state of ionization
of certain drugs and may therefore afect the re‑absorption
from the renal tubule.[91]
In particular, if the pH of the urine is alkaline the absorption
of acidic drugs is reduced, while, in the presence of an
acidic pH, basic drug absorption is reduced.
The changes in urinary pH, however, assume practical
importance only if the pKa of the drug, i.e., the pH at which
50% of the molecules in solution is present in ionized form,
is between 7.5 and 10.5 for the bases, and between 3.0 and
7.5 for acids.
In fact, the pKa values can cause appreciable changes in
the degree of dissociation of the drug. Compounds such
as ammonium chloride, tromethamine and diuretics, being
able to change urine pH, may afect the excretion of several
acidic and basic drugs,[15] and this interaction may be used
to facilitate the removal of drugs from the body. On the
contrary, the interaction between diuretics and lithium salts
can still have negative efects on the patient.
Lithium is a monovalent cation whose excretion is
inluenced by changes of serum sodium. Therefore, a high
excretion of sodium induced by chronic treatment with
some diuretics such as thiazides, may increase lithium
re‑absorption, causing serious toxic efects from relative
over dosage.[92,93]
Some acidic and basic drugs with the high degree of
ionization are transferred through the epithelium of the
renal tubule by active transport. The speed transfer of
molecules depends on the availability of the transporter,
a protein that allows the transfer through the cellular
membranes. Therefore, when two drugs are substrate of
the same transmembrane transporter they can complete
each other, up to the saturation of transporter capacity.
At that time, the rate of elimination approaches to a zero
order (saturable) process.
Journal of Research in Medical Sciences
| July 2013 |
Caterina, et al.: Pharmacokinetic drug‑drug interaction
Strategy to prevent pharmacokinetic DDI
The Summary of Product Characteristics (SPCs) represents
the primary source of information about DDIs for health
care professionals. Unfortunately, DDI cannot be listed
exhaustively. consequently the information on potential
DDIs may be insuiciently described, due to the limited
space in the SPC.
In fact, in an Italian study cross‑sectional study, was found
that the 3.0% of PPI users were exposed to potential DDI
within 1 year of follow‑up, according to the risk described in
the Italian SPCs of PPIs, but this proportion was three‑fold
higher (9.0%) when information about DDI risk with PPIs,
reported on Drugdex, was considered.[94]
Therefore, reports on DDI that consider diferent sources
updated on the basis of current evidence from the literature
should be useful to evaluate a possible risk of DDI
particularly in elderly patients with poly‑therapy.
Moreover, even if not always available and feasible, the
adoption of therapeutic drug monitoring protocols in
the above reported patients (i.e., elderly people with
comorbidities treated with multiple drugs) should be
considered an important instrument to decrease the
occurrence and magnitude of DDIs that could induce either
an increase in health costs for the Health system and a legal
responsibility for the clinicians.
Therefore, we hope that the National Health System plan a
strategy intervention to keep physicians adequately aware
of potential DDI, with particular regard to widely used
medications.
However, may be underlined that only two drugs are able
to induce the development of a DDI even if this clinical
relevance is related to the pharmacology of each drug. In
fact, a DDI will be able to induce a clinically relevant efect
in presence of drugs with a low therapeutic index, a long
half‑life and a higher bound with plasma proteins.
Moreover, it is important to underline that the development
of DDI is not a problem a class of drug but of a single drug
and this problem could be under estimated considering
the SPC only.
REFERENCES
1.
2.
3.
4.
5.
6.
7.
However, in this time, reports on DDIs that consider diferent
sources updated on the basis of current evidence from the
literature should be useful to evaluate a possible risk of DDI
particularly in elderly patients with poly‑therapy.
Previously it has been reported that genetic polymorphism of
CYP enzymes played a signiicant role in the clinical efects of
drug treatment[7,95,96] as well as in the development of DDIs.[97]
In this light, even if not always available and feasible, both
the adoption of therapeutic drug monitoring in patients
with multiple drug treatment and in vitro techniques to
predict the role of CYP enzymes polymorphism in DDIs,
should be considered an important instrument to decrease
the occurrence and magnitude of DDIs.
9.
10.
11.
12.
CONCLUSIONS
DDIs represent a common clinical problem during the
management of patients treated with several drugs.
| July 2013 |
8.
13.
Moore N, Biour M, Paux G, Loupi E, Begaud B, Boismare F, et al.
Adverse drug reaction monitoring: Doing it the French way. Lancet
1985;2:1056‑8.
Lee CE, Zembower TR, Fotis MA, Postelnick MJ, Greenberger PA,
Peterson LR, et al. The incidence of antimicrobial allergies
in hospitalized patients: Implications regarding prescribing
paterns and emerging bacterial resistance. Arch Intern Med
2000;160:2819‑22.
Bordet R, Gautier S, Le Louet H, Dupuis B, Caron J. Analysis of
the direct cost of adverse drug reactions in hospitalised patients.
Eur J Clin Pharmacol 2001;56:935‑41.
Gallelli L, Ferreri G, Colosimo M, Pirritano D, Guadagnino L,
Pelaia G, et al. Adverse drug reactions to antibiotics observed in two
pulmonology divisions of catanzaro, Italy: A six‑year retrospective
study. Pharmacol Res 2002;46:395‑400.
Gallelli L, Ferreri G, Colosimo M, Pirritano D, Flocco MA,
Pelaia G, et al. Retrospective analysis of adverse drug reactions
to bronchodilators observed in two pulmonary divisions of
Catanzaro, Italy. Pharmacol Res 2003;47:493‑9.
Gallelli L, Colosimo M, Pirritano D, Ferraro M, De Fazio S,
Marigliano NM, et al. Retrospective evaluation of adverse drug
reactions induced by nonsteroidal anti‑inlammatory drugs. Clin
Drug Investig 2007;27:115‑22.
Gallelli L, Colosimo M, Tolotta GA, Falcone D, Luberto L,
Curto LS, et al. Prospective randomized double‑blind trial of
racecadotril compared with loperamide in elderly people with
gastroenteritis living in nursing homes. Eur J Clin Pharmacol
2010;66:137‑44.
Franceschi A, Tuccori M, Bocci G, Vannozzi F, Di Paolo A,
Barbara C, et al. Drug therapeutic failures in emergency
department patients. A university hospital experience. Pharmacol
Res 2004;49:85‑91.
Johnell K, Klarin I. The relationship between number of drugs
and potential drug‑drug interactions in the elderly: A study of
over 600,000 elderly patients from the Swedish Prescribed Drug
Register. Drug Saf 2007;30:911‑8.
Siniscalchi A, Gallelli L, Avenoso T, Squillace A, De Sarro G. Efects
of carbamazepine/oxycodone coadministration in the treatment
of trigeminal neuralgia. Ann Pharmacother 2011;45:e33.
Canu B, Fioravanti A, Orlandi P, Di Desidero T, Alì G, Fontanini G,
et al. Irinotecan synergistically enhances the antiproliferative and
proapoptotic efects of axitinib in vitro and improves its anticancer
activity in vivo. Neoplasia 2011;13:217‑29.
Rochon PA, Gurwitz JH. Optimising drug treatment for elderly
people: The prescribing cascade. BMJ 1997;315:1096‑9.
Mantia G, Provenzano G. Rilevanza clinica delle interazioni
farmacologiche di tipo farmacocinetico. Acta Medica Mediterr
2008;24:23‑27.
Journal of Research in Medical Sciences
606
Caterina, et al.: Pharmacokinetic drug‑drug interaction
14. Krishna G, Moton A, Ma L, Medlock MM, McLeod J.
Pharmacokinetics and absorption of posaconazole oral suspension
under various gastric conditions in healthy volunteers. Antimicrob
Agents Chemother 2009;53:958‑66.
15. Ogawa R, Echizen H. Drug‑drug interaction proiles of proton
pump inhibitors. Clin Pharmacokinet 2010;49:509‑33.
16. Bokor‑Bratić M, Brkanić T. Clinical use of tetracyclines in the
treatment of periodontal diseases. Med Pregl 2000;53:266‑71.
17. Ogawa R, Echizen H. Clinically signiicant drug interactions with
antacids: An update. Drugs 2011;71:1839‑64.
18. Seedher N, Agarwal P. Effect of metal ions on some
pharmacologically relevant interactions involving luoroquinolone
antibiotics. Drug Metabol Drug Interact 2010;25:17‑24.
19. Scaldaferri F, Pizzoferrato M, Ponziani FR, Gasbarrini G,
Gasbarrini A. Use and indications of cholestyramine and bile acid
sequestrants. Intern Emerg Med 2011;8.
20. Phillips WA, Ratchford JM, Schultz JR. Effects of colestipol
hydrochloride on drug absorption in the rat II. J Pharm Sci
1976;65:1285‑91.
21. Lee HT, Lee YJ, Chung SJ, Shim CK. Efect of prokinetic agents,
cisapride and metoclopramide, on the bioavailability in humans
and intestinal permeability in rats of ranitidine, and intestinal
charcoal transit in rats. Res Commun Mol Pathol Pharmacol
2000;108:311‑23.
22. Johnson BF, Bustrack JA, Urbach DR, Hull JH, Marwaha R. Efect of
metoclopramide on digoxin absorption from tablets and capsules.
Clin Pharmacol Ther 1984;36:724‑30.
23. Wynn GH, Sandson NB, Cozza KL. Gastrointestinal medications.
Psychosomatics 2007;48:79‑85.
24. Silverman JA, Thorgeirsson SS. Regulation and function of the
multidrug resistance genes in liver. Prog Liver Dis 1995;13:101‑23.
25. Thummel KE, Wilkinson GR. In vitro and in vivo drug interactions
involving human CYP3A. Annu Rev Pharmacol Toxicol
1998;38:389‑430.
26. Rushing DA, Raber SR, Rodvold KA, Piscitelli SC, Plank GS,
Tewksbury DA. The efects of cyclosporine on the pharmacokinetics
of doxorubicin in patients with small cell lung cancer. Cancer
1994;74:834‑41.
27. Shi Z, Tiwari AK, Shukla S, Robey RW, Singh S, Kim IW, et al.
Sildenail reverses ABCB1‑and ABCG2‑mediated chemotherapeutic
drug resistance. Cancer Res 2011;71:3029‑41.
28. Sudlow G, Birkett DJ, Wade DN. The characterization of
two specific drug binding sites on human serum albumin.
Mol Pharmacol 1975;11:824‑32.
29. Kragh‑Hansen U, Chuang VT, Otagiri M. Practical aspects of
the ligand‑binding and enzymatic properties of human serum
albumin. Biol Pharm Bull 2002;25:695‑704.
30. Oliva F, Gallelli L. Ibuprofen pharmacology and its implications
for musculoskeletal disorders. Funct Neurol 2010;25:20.
31. Pozzi A, Gallelli L. Pain management for dentists: The role of
ibuprofen. Ann Stomatol (Roma) 2011;2:3‑24.
32. Guengerich FP. Characterization of human cytochrome P450
enzymes. FASEB J 1992;6:745‑8.
33. Nelson DR, Kamataki T, Waxman DJ, Guengerich FP,
Estabrook RW, Feyereisen R, et al. The P450 superfamily: Update
on new sequences, gene mapping, accession numbers, early trivial
names of enzymes, and nomenclature. DNA Cell Biol 1993;12:1‑51.
34. Nebert DW, Nelson DR, Coon MJ, Estabrook RW, Feyereisen R,
Fujii‑Kuriyama Y, et al. The P450 superfamily: Update on new
sequences, gene mapping, and recommended nomenclature.
DNA Cell Biol 1991;10:1‑14.
35. Nakamura K, Goto F, Ray WA, McAllister CB, Jacqz E,
Wilkinson GR, et al. Interethnic differences in genetic
polymorphism of debrisoquin and mephenytoin hydroxylation
607
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
between Japanese and Caucasian populations. Clin Pharmacol
Ther 1985;38:402‑8.
Døssing M, Pilsgaard H, Rasmussen B, Poulsen HE. Time course
of phenobarbital and cimetidine mediated changes in hepatic drug
metabolism. Eur J Clin Pharmacol 1983;25:215‑22.
Murray M. Drug‑mediated inactivation of cytochrome P450. Clin
Exp Pharmacol Physiol 1997;24:465‑70.
Murray M. P450 enzymes. Inhibition mechanisms, genetic
regulation and effects of liver disease. Clin Pharmacokinet
1992;23:132‑46.
Lillibridge JH, Liang BH, Kerr BM, Webber S, Quart B, Shety BV,
et al. Characterization of the selectivity and mechanism of human
cytochrome P450 inhibition by the human immunodeiciency
virus‑protease inhibitor nelinavir mesylate. Drug Metab Dispos
1998;26:609‑16.
Suton D, Butler AM, Nadin L, Murray M. Role of CYP3A4 in
human hepatic diltiazem N‑demethylation: Inhibition of CYP3A4
activity by oxidized diltiazem metabolites. J Pharmacol Exp Ther
1997;282:294‑300.
Wagner F, Kalusche D, Trenk D, Jähnchen E, Roskamm H. Drug
interaction between propafenone and metoprolol. Br J Clin
Pharmacol 1987;24:213‑20.
Gareri P, De Fazio P, Gallelli L, De Fazio S, Davoli A, Seminara G,
et al. Venlafaxine‑propafenone interaction resulting in
hallucinations and psychomotor agitation. Ann Pharmacother
2008;42:434‑8.
Markowitz JS, Wells BG, Carson WH. Interactions between
antipsychotic and antihypertensive drugs. Ann Pharmacother
1995;29:603‑9.
Preskorn SH, Alderman J, Chung M, Harrison W, Messig M,
Harris S. Pharmacokinetics of desipramine coadministered with
sertraline or luoxetine. J Clin Psychopharmacol 1994;14:90‑8.
Zomorodi K, Houston JB. Efect of omeprazole on diazepam
disposition in the rat: In vitro and in vivo studies. Pharm Res
1995;12:1642‑6.
Meyer UA. Interaction of proton pump inhibitors with
cytochromes P450: Consequences for drug interactions. Yale J Biol
Med 1996;69:203‑9.
Zomorodi K, Houston JB. Diazepam‑omeprazole inhibition
interaction: An in vitro investigation using human liver
microsomes. Br J Clin Pharmacol 1996;42:157‑62.
Levy RH. Cytochrome P450 isozymes and antiepileptic drug
interactions. Epilepsia 1995;36:S8‑13.
Jones TE, Morris RG, Mathew TH. Diltiazem‑cyclosporin
pharmacokinetic interaction – Dose‑response relationship. Br J Clin
Pharmacol 1997;44:499‑504.
Jones TE, Morris RG. Diltiazem does not always increase blood
cyclosporin concentration. Br J Clin Pharmacol 1996;42:642‑4.
Campana C, Regazzi MB, Buggia I, Molinaro M. Clinically
signiicant drug interactions with cyclosporin. An update. Clin
Pharmacokinet 1996;30:141‑79.
Gilard M, Arnaud B, Cornily JC, Le Gal G, Lacut K, Le Calvez G,
et al. Influence of omeprazole on the antiplatelet action of
clopidogrel associated with aspirin: The randomized, double‑blind
OCLA (Omeprazole CLopidogrel Aspirin) study. J Am Coll
Cardiol 2008;51:256‑60.
Ho PM, Maddox TM, Wang L, Fihn SD, Jesse RL, Peterson ED,
et al. Risk of adverse outcomes associated with concomitant use of
clopidogrel and proton pump inhibitors following acute coronary
syndrome. JAMA 2009;301:937‑44.
Gareri P, De Fazio P, Cotroneo A, Lacava R, Gallelli L, De
Fazio S, et al. Anticholinergic drug‑induced delirium in an
elderly Alzheimer’s dementia patient. Arch Gerontol Geriatr
2007;44:199‑206.
Journal of Research in Medical Sciences
| July 2013 |
Caterina, et al.: Pharmacokinetic drug‑drug interaction
55. Ohyama K, Nakajima M, Nakamura S, Shimada N, Yamazaki H,
Yokoi T. A significant role of human cytochrome P450 2C8
in amiodarone N‑deethylation: An approach to predict the
contribution with relative activity factor. Drug Metab Dispos
2000;28:1303‑10.
56. Muirhead GJ, Wulf MB, Fielding A, Kleinermans D, Buss N.
Pharmacokinetic interactions between sildenail and saquinavir/
ritonavir. Br J Clin Pharmacol 2000;50:99‑107.
57. Page RL 2nd, Mueller SW, Levi ME, Lindenfeld J. Pharmacokinetic
drug‑drug interactions between calcineurin inhibitors and
proliferation signal inhibitors with anti‑microbial agents:
Implications for therapeutic drug monitoring. J Heart Lung
Transplant 2011;30:124‑35.
58. Sansone‑Parsons A, Krishna G, Martinho M, Kantesaria B, Gelone S,
Mant TG. Efect of oral posaconazole on the pharmacokinetics of
cyclosporine and tacrolimus. Pharmacotherapy 2007;27:825‑34.
59. Kapil RP, Cipriano A, Michels GH, Perrino P, O’Keefe SA, Shet MS,
et al. Effect of ketoconazole on the pharmacokinetic profile
of buprenorphine following administration of a once‑weekly
buprenorphine transdermal system. Clin Drug Investig
2012;32:583‑92.
60. Periti P, Mazzei T, Mini E, Novelli A. Pharmacokinetic drug
interactions of macrolides. Clin Pharmacokinet 1992;23:106‑31.
61. Gallelli L, Giofrè V, Vero G, Gallelli A, Roccia F, Naty S, et al.
Clarithromycin in the Treatment of Legionella pneumophila
Pneumonia Associated with Multiorgan Failure in a Previously
Healthy Patient. Clin Drug Investig 2005;25:485‑90.
62. Somogyi A, Gugler R. Drug interactions with cimetidine. Clin
Pharmacokinet 1982;7:23‑41.
63. Somogyi A, Muirhead M. Pharmacokinetic interactions of
cimetidine 1987. Clin Pharmacokinet 1987;12:321‑66.
64. Garraffo R, Lavrut T, Ferrando S, Durant J, Rouyrre N,
MacGregor TR, et al. Efect of tipranavir/ritonavir combination
on the pharmacokinetics of tadalail in healthy volunteers. J Clin
Pharmacol 2011;51:1071‑8.
65. Gruer PJ, Vega JM, Mercuri MF, Dobrinska MR, Tobert JA.
Concomitant use of cytochrome P450 3A4 inhibitors and
simvastatin. Am J Cardiol 1999;84:811‑5.
66. Martin J, Krum H. Cytochrome P450 drug interactions within the
HMG‑CoA reductase inhibitor class: Are they clinically relevant?
Drug Saf 2003;26:13‑21.
67. Gallelli L, Ferraro M, Spagnuolo V, Rende P, Mauro GF, De Sarro G.
Rosuvastatin‑induced rhabdomyolysis probably via CYP2C9
saturation. Drug Metabol Drug Interact 2009;24:83‑7.
68. Venkatesan K. Pharmacokinetic drug interactions with rifampicin.
Clin Pharmacokinet 1992;22:47‑65.
69. Lee KH, Shin JG, Chong WS, Kim S, Lee JS, Jang J, et al. Time
course of the changes in prednisolone pharmacokinetics ater
co‑administration or discontinuation of rifampin. Eur J Clin
Pharmacol 1993;45:287‑9.
70. Burger DM, Meenhorst PL, Koks CH, Bejnen JH. Pharmacokinetic
interaction between rifampin and zidovudine. Antimicrob Agents
Chemother 1993;37:1426‑31.
71. Grange JM, Winstanley PA, Davies PD. Clinically signiicant drug
interactions with antituberculosis agents. Drug Saf 1994;11:242‑51.
72. Koselj M, Bren A, Kandus A, Kovac D. Drug interactions between
cyclosporine and rifampicin, erythromycin, and azoles in
kidney recipients with opportunistic infections. Transplant Proc
1994;26:2823‑4.
73. Holtbecker N, Fromm MF, Kroemer HK, Ohnhaus EE,
Heidemann H. The nifedipine‑rifampin interaction. Evidence
for induction of gut wall metabolism. Drug Metab Dispos
1996;24:1121‑3.
74. Li AP, Reith MK, Rasmussen A, Gorski JC, Hall SD, Xu L, et al.
| July 2013 |
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
91.
92.
Primary human hepatocytes as a tool for the evaluation of
structure‑activity relationship in cytochrome P450 induction
potential of xenobiotics: Evaluation of rifampin, rifapentine and
rifabutin. Chem Biol Interact 1997;107:17‑30.
Fromm MF, Busse D, Kroemer HK, Eichelbaum M. Diferential
induction of prehepatic and hepatic metabolism of verapamil by
rifampin. Hepatology 1996;24:796‑801.
Fleishaker JC, Pearson LK, Peters GR. Gender does not afect the
degree of induction of tirilazad clearance by phenobarbital. Eur J
Clin Pharmacol 1996;50:139‑45.
Rambeck B, Specht U, Wolf P. Pharmacokinetic interactions of the
new antiepileptic drugs. Clin Pharmacokinet 1996;31:309‑24.
Backman JT, Olkkola KT, Ojala M, Laaksovirta H, Neuvonen PJ.
Concentrations and efects of oral midazolam are greatly reduced
in patients treated with carbamazepine or phenytoin. Epilepsia
1996;37:253‑7.
Cropp JS, Bussey HI. A review of enzyme induction of warfarin
metabolism with recommendations for patient management.
Pharmacotherapy 1997;17:917‑28.
Siniscalchi A, Gallelli L, De Sarro G, Malferrari G, Santangelo E.
Antiepileptic drugs for central post‑stroke pain management.
Pharmacol Res 2012;65:171‑5.
Watkins PB, Wrighton SA, Schuetz EG, Molowa DT, Guzelian PS.
Identiication of glucocorticoid‑inducible cytochromes P‑450 in the
intestinal mucosa of rats and man. J Clin Invest 1987;80:1029‑36.
Siniscalchi A, Gallelli L, Calabrò G, Tolota GA, De Sarro G.
Phenobarbital/Lamotrigine coadministration‑induced blood
dyscrasia in a patient with epilepsy. Ann Pharmacother
2010;44:2031‑4.
Carrillo Norte JA. Pharmacokinetic process: Does the site of drug
action? Excretion of drugs. Rev Enferm 2011;34:24‑31.
Kido Y, Matsson P, Giacomini KM. Proiling of a prescription drug
library for potential renal drug‑drug interactions mediated by the
organic cation transporter 2. J Med Chem 2011;54:4548‑58.
Kristensen MB. Drug interactions and clinical pharmacokinetics.
Clin Pharmacokinet 1976;1:22.
Ronchera CL, Hernández T, Peris JE, Torres F, Granero L,
Jiménez NV, et al. Pharmacokinetic interaction between high‑dose
methotrexate and amoxycillin. Ther Drug Monit 1993;15:375‑9.
Hill G, Cihlar T, Oo C, Ho ES, Prior K, Wiltshire H, et al. The
anti‑inluenza drug oseltamivir exhibits low potential to induce
pharmacokinetic drug interactions via renal secretion‑correlation
of in vivo and in vitro studies. Drug Metab Dispos 2002;30:13‑9.
Wu H, Liu M, Wang S, Feng W, Yao W, Zhao H, et al.
Pharmacokinetic properties and bioequivalence of two compound
formulations of 1500 mg ampicillin (1167 mg)/probenecid (333 mg):
A randomized‑sequence, single‑dose, open‑label, two‑period
crossover study in healthy Chinese male volunteers. Clin Ther
2010;32:597‑606.
Ito S, Kusuhara H, Yokochi M, Toyoshima J, Inoue K, Yuasa H,
et al. Competitive inhibition of the luminal elux by multidrug
and toxin extrusions, but not basolateral uptake by organic
cation transporter 2, is the likely mechanism underlying the
pharmacokinetic drug‑drug interactions caused by cimetidine in
the kidney. J Pharmacol Exp Ther 2012;340:393‑403.
Nies AT, Hofmann U, Resch C, Schaefeler E, Rius M, Schwab M.
Proton pump inhibitors inhibit metformin uptake by organic cation
transporters (OCTs). PLoS One 2011;6:e22163.
Fagerholm U. Prediction of human pharmacokinetics‑renal
metabolic and excretion clearance. J Pharm Pharmacol
2007;59:1463‑71.
Handler J. Lithium and antihypertensive medication:
A potentially dangerous interaction. J Clin Hypertens (Greenwich)
2009;11:738‑42.
Journal of Research in Medical Sciences
608
Caterina, et al.: Pharmacokinetic drug‑drug interaction
93. Amdisen A. Lithium and drug interactions. Drugs 1982;24:133‑9.
94. Triirò G, Corrao S, Alacqua M, Moreti S, Tari M, Caputi AP,
et al. Interaction risk with proton pump inhibitors in general
practice: Signiicant disagreement between diferent drug‑related
information sources. Br J Clin Pharmacol 2006;62:582‑90.
95. Gallelli L, Galasso O, Urzino A, Saccà S, Falcone D, Palleria C, et al.
Characteristics and clinical implications of the pharmacokinetic
proile of Ibuprofen in patients with knee osteoarthritis. Clin Drug
Investig 2012;32:827‑33.
609
96. De Fazio S, Gallelli L, De Siena A, De Sarro G, Scordo MG. Role of
CYP3A5 in abnormal clearance of methadone. Ann Pharmacother
2008;42:893‑7.
97. Spina E, Triiro G. Preventing drug interactions with antidepressants
in the elderly. Aging Health 2007;3:13.
Source of Support: we did not receive any found for this research, Conlict
of Interest: None declared.
Journal of Research in Medical Sciences
| July 2013 |