DRUG INTERACTIONS LINKED

TO TRANSPORTERS

Prarthna Yadav
26/MPH/DPSRU/2018
INDUSTRIAL PHARMACY
CONTENTS

INTRODUCTION
BASIC MECHANISM OF
TRANSPORT
MEMBRANE TRANSPORTERS
TYPES
DRUG DRUG INTERACTIONS
 INTRODUCTION

 Drug transporters mediate the uptake and efflux of a broad variety of drugs and drug
metabolites

 Drug–drug interactions is induction or inhibition of drug transporters that mediate the

cellular uptake and efflux of xenobiotic

 Drug transporters of the small intestine, liver and kidney are major determinants of the
pharmacokinetic profile of drugs

 Localized in organs such as small intestine, liver, and kidney, which are critical for drug
absorption and elimination

 Inhibition or induction of drug transporters by co administered drugs can alter

pharmacokinetics and pharmacodynamics of the victim drugs
BASIC MECHANISM OF TRANSPORT

The transport of drug across the membrane

occur through one or more of the following
processes

 Simple diffusion (passive diffusion )

 Facilitated diffusion

 Active transport

 Endocytosis
 BASIC MECHANISM OF TRANSPORT
FACILIATED DIFFUSION
SIMPLE DIFFUSION

Facilitated diffusion is the process of spontaneous

Simple diffusion is the process by passive transport of molecules or ions across a
which solutes are moved along a biological membrane via specific transmembrane
concentration gradient in a solution or integral proteins
across a semipermeable membrane
BASIC MECHANISM OF TRANSPORT
ACTIVE TRANSPORT ENDOCYTOSIS

The movement of molecules across a A cellular process in which substances are

membrane from a region of their lower brought into the cell.
concentration to a region of their The material to be internalized is surrounded
higher concentration—against the by an area of plasma membrane, which then
concentration gradient buds off inside the cell to form a vesicle
containing the ingested material
Active transport requires cellular
energy to achieve this movement
MEMBRANE TRANSPORTER

Ꙭ Transporters (membrane transport/carrier

proteins) are specialized membrane-spanning
proteins that assist in the movement of ions,
peptides, small molecules, lipids and
macromolecules across a biological
membrane.
Ꙭ Drug transporters are now well recognized
determinants of drug disposition and effects
Ꙭ Functionally, they can be classified into
transporters mediating the uptake of drugs
into cells and transporters mediating the
export of drugs or drug metabolites out of
cells
 TYPES OF TRANSPORTERS
EFFLUX TRANSPORTERS
Uptake transporters
 Members of the ATP binding cassette (ABC) transporter
Members of the solute carrier (SLC) family
family *exception is the MATE (multidrug and toxin
extrusion) proteins, also members of the SLC transporter
Mediating the transport of substances from outside superfamily
into cells
 Export proteins transporting substances out of cells
Members are
 Members are
1. OAT : organic anion tansporter
1. MDR/TAP FAMILY : Multi drug resistance protein
2. OCT (SLC FAMILY SLC21/22/0) : organic cation
transporter
2. MRP2 PROTEIN

Transport a variety of amphipathic substances,

3. BCRP PROTEIN
including several endogenously synthesized
metabolites such as bile acids, thyroid hormones,
or hormone conjugates ,antibiotics, 4. MATE
chemotherapeutic agents, antihistaminic drugs, and
diuretics
5. P- gp
MEMBRANE TRANSPORTERS
DRUG DRUG INTERACTIONS
INTESTINAL DRUG TRANSPORTERS

Pass

Gut wall
Drug Portal vein
mucosa
• Consists of polarized enterocytes

• In these cells, several drug

transporters have been identified
INTESTINAL DRUG TRANSPORTERS

UPTAKE TRANSPORTERS

Transporters of the SLC family facilitate the

cellular uptake of their substrates

 ALISKIREN has been described as a substrate

of intestinal p-gp and OATP2B1
 A strong increase of aliskiren plasma
concentrations when coadministered with
itraconazole
 Itraconazole an inhibitor of p-gp

 The p-gp inducer RIFAMPIN, conversely,

caused a marked reduction of ALISKIREN
bioavailability
INTESTINAL DRUG TRANSPORTER

Efflux transporter

 ABC transporters such as p-gp

mediate the ATP-dependent efflux
of drugs back into the intestinal
lumen

 In 1999, Greiner et al. reported a study

that investigated the effect of treatment
with the antibiotic rifampin on digoxin
pharmacokinetics
 Duodenal biopsies demonstrated a 3.5-
fold increase of p-gp expression
 Rifampin reduces oral digoxin
bioavailability by the induction of intestinal
p-gp
INTESTINAL DRUG TRANSPORTER
 HEPATIC TRANSPORTERS

The liver is a major contributor to

first – pass elimination for orally
as well as for plasma clearance
Rate 1500 ml/ min
Major part : Portal vein 70-80%
Minor part: Hepatic artery
 HEPATIC TRANSPORTERS
Uptake transporter
Transporters that are localized at the sinusoidal membrane of hepatocytes mediate the uptake
OATP1B1 , OATPIB3 , OAT2B1 & NTCP (SODIUM/TAUROCHOLATE COTRANSPORTING POLYPEPTIDE)
The fibrate gemfibrozil and its major metabolite gemfibrozil-1-o-b-glucuronide are moderate inhibitors of
OATP1B1 ,OATP1B3

• Statins are widely used to reduce the occurrence of cardiovascular events and death in patients at risk
• Statins have toxic muscle side effects which is rhabdomyolysis
• statins are substrates of drug transporters in the intestine, liver and kidney; all of which may influence statin
plasma concentrations
• concomitant oral administration of gemfibrozil (1200 mg daily for 3 days) with pravastatin (40 mg single dose
on day 3) caused an increase of pravastatin AUC and Cmax by 102 and 81%, respectively

Increases of statin plasma concentrations have been observed following the coadministration of cyclosporine
HEPATIC TRANSPORTERS
EFFLUX TRANSPORTER
 Atp-dependent efflux transporters and the multidrug and toxin extrusion protein (MATE) 1
• Driven by the transmembraneous proton gradient, are localized in the canalicular membrane of
the hepatocyte
• Concomitant administration of quinidine or verapamil reduced the biliary digoxin clearance in
humans by approximately 45%
• Quinidine and verapamil have been identified as potent inhibitors of p-gp-mediated digoxin
transport

• MATE1 is believed to be important for the renal tubular secretion of cationic drugs such as
metformin
• MATE1 knockout or inhibition by pyrimethamine caused a marked increase of metformin liver tissue
concentration
 RENAL TRANSPORTERS

o Drugs are eliminated in the kidney by glomerular filtration and/or tubular secretion

o Uptake transporters in the basolateral membrane & export transporters in the luminal membrane of the
renal tubule cells are involved in the tubular secretion of their substrates

o Inhibition of these transport processes may decrease the renal clearance of drugs

o Inhibition of cellular uptake may improve the benefit–risk ratio of nephrotoxic drugs
RENAL TRANSPORTERS
 RENAL TRANSPORTERS

UPTAKE TRANSPORTERS

• Inhibition of organic anion transporters (oats) or the organic cation transporter (OCT) 2 at the basolateral
membrane of renal proximal tubule cells decreases the cellular uptake of their substrates
• The uricosuric drug probenecid is the prototypical inhibitor of the organic anion transporters OAT1 and
OAT3
• Probenecid was originally developed to prolong the plasma half-life of the antibiotic benzylpenicillin
• Benzylpenicillin is a substrate of OAT3
• Probenecid was identified as being a clinically relevant inhibitor of OAT1 and OAT3
• Concomitant administration of probenecid decreased the renal clearance of methotrexate and
furosemide
• A beneficial interaction that reduces the risk of adverse drug reactions has been described for the
combination of probenecid and cidofovir
RENAL TRANSPORTERS

UPTAKE TRANSPORTER

• OCT2 transports a broad spectrum of drugs including, for example, amantadine , H2-receptor blockers ,
metformin

• Inhibition of oct2-mediated cisplatin uptake could have renoprotective effects in cancer therapy
• Tyrosine kinase inhibitor imatinib inhibits cisplatin-induced cytotoxicity
• In vivo studies in mice and rats demonstrated a partial protection from cisplatin-induced nephrotoxicity by
cimetidine and imatinib
 RENAL TRANSPORTERS
EFFLUX TRANSPORTERS

• In 2005, Otsuka et al. described MATE1 as a transport protein that is localized at the canalicular membrane of
hepatocytes and at the luminal membrane of renal tubule cells
• Depending on an oppositely directed proton gradient as a driving force, MATE1 may either act as an uptake
or efflux transporter
• Extracellular alkalinization or intracellular acidification increases MATE1-mediated uptake
• An increased accumulation of metformin in kidney tissue was also observed in mice that were treated with
the MATE1 inhibitor pyrimethamine
• An important and well characterized export protein at the luminal membrane of renal proximal tubule cells is
P-gp
• Concomitant administration of the P-gp inhibitor quinidine decreases the renal clearance of digoxin
• Renal digoxin clearance was also decreased by other P-gp inhibitors such as ritonavir or itraconazole
RENAL TRANSPORTERS

EFFLUX TRANSPORTERS

• Localization of bcrp at the luminal membrane of renal proximal tubule cells has been reported

• Important for the renal secretion of drugs

• Vlaming et al. Found that bcrp mediated a substantial urinary excretion of methotrexate

• Uric acid has been identified as substrate of BCR

• Recent data demonstrate an association of polymorphisms in the abcg2 gene (encoding BCRP) with
increased uric acid levels, as well as with the risk of developing gout . Therefore, inhibition of renal
BCRP by concomitantly administered drugs might be a risk factor for gout.
REFERENCES
• Transporters and Drug-Drug Interactions: Important Determinants of Drug
Disposition and Effectss
Jörg König, Fabian Müller, and Martin F. Fromm Institute of Experimental and
Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität
Erlangen-Nürnberg, Germany
• Transporter-mediated drug–drug interactions
Fabian Müller1 & Martin F Fromm†1 1Institute of Experimental & Clinical
Pharmacology & Toxicology, Friedrich-Alexander-Universität Erlangen-
Nürnberg, Fahrstrasse 17, 91054 Erlangen, Germany