Adrenoreceptors

expected to have a higher incidence of sensitization and Bult, A., U. Uitterdijk, J. D., Klasen, H. B.
(1979)
allergies. Such products are therefore less suitable for Transition Met. Chem. 4: 285-288
topical application. The zinc and cerium sulphadiazine Coenegracht. P. M. J., Franke. J. P., Metting, H. J.
samples used by Fox et al (1976, 1978) are identical to (1973) Anal. Chim. Acta 65: 375-384
our products. In accordance with our conclusions is Fox, C. L. (1968) Arch. Surg. 96: 184-188
the finding of Fox et al (1976) that zinc sulphadiazine Fox, C. L., Modak, Sh. M., Stanford, J. W. (1976)
Surg. Gynecol. Obstet. 42: 553-559
was partially blocked by p-aminobenzoic acid Fox, C. L. (1977) Pahlavi Med. J. 8: 45-64
(sulphadiazine is blocked) in contrast with silver Fox, C. L., Modak, Sh. M., Stanford, J. W. (1978)
sulphadiazine which is not blocked. In non-aqueous Burns 4: 233-239
~~-~
media it is possible to prepare Zn(SD)*separately. Fox, C. L., Modak, Sh. M., Stanford, J. W., Fox, P. L.
(1979) Scand. J. Plast. Reconstr. Surg. 13: 89-94
REFERENCES
Narang. K. K.. Gupta, J. K. (1976) J. Inorg. Nucl.
Bleumink, E., Klokke, A. H. (1971) Lancet: 1425 Chem. 38: 589-590
Bult, A. Klasen, H. B. (1978) J. Pharm. Sci. 67: 284- Narang, K. K., Gupta, J. K. (1977) Transition Met.
287 Chem. 2: 181-183
J. Pharm. Pharmacol. 1981, 33: 172-173 0022-3573181 1030172-02 $02.50/0

Communicated December 10, 1980 @ 1981 J. Pharm. Pharmacol.
An investigation of the comparative liposolubilities of p-adrenoceptor

-
blocking agents
P. B. WOODS*,M. L. ROBINSON,
E. R. Squibb & Sons Ltd, International Development Laboratories Moreton, Wirrd,
Merseyside. U.K.
Currently there are nine 8-adrenoceptor blocking drugs The n-octanol and the phosphate buffer were pm
and one a/,!?-blocker available for clinical use in the U.K. equilibrated by shaking together, separating and
The pharmacokinetics of the group vary significantly storing until required.
from one member to another. 8-Blockers can be highly The drug sample was dissolved in the phosphate
or only minimally bound to plasma proteins, their buffer at an appropriate level and an aliquot (5 ml) of
distribution varies from one drug to another and plasma the buffer was shaken with a suitable volume of the
half-life can be as little as 2 h (oxprenolol) or as long as saturated n-octanol (250 ml for atenolol; 50 ml for
24 h (nadolol). They can be almost entirely metabolized sotalol and nadolol; 2.5 ml for propranolol and
(propranolol) or be excreted unchanged (nadolol). One labetalol; 5 ml for all other compounds) for 1 h. The
of the major determinants of the pharmacokinetic mixture was then left to separate for 30 min, centrifuged
profile of a drug is its liposolubility (Kubinyi 1979). for 1 min and the layers separated. The U.V. absorption
Highly liposoluble /?-blockers undergo a high degree of of the aqueous layer was measured at an appropriate
first pass metabolism in the liver, are highly bound to wavelength, and compared with the original aqueous
plasma proteins and concentrate in the central nervous solution before partition.
system. The 8-adrenoceptor blocking drugs tested varied
Only incomplete and fragmented partition coefficient widely in their lipophilic characteristics. Results at room
data is available for 8-blockers and the current work is temperature (20 "C), pH 7 and at 37 "C, pH 7 and
aimed at obtaining directly comparable data. We have pH 7.4 are presented in Table 1.
investigated their comparative liposolubilities by
determination of their distribution between n-octanol
and aqueous buffer (distribution coefficients).
The drugs used were: nadolol, propranolol hydro- Table 1. Distribution coefficients n-octanol/buffer.
chloride, oxprenolol hydrochloride, sotalol hydro-
chloride, acebutolol hydrochloride, labetalol hydro- Previously
publishedg Distribution coefficients at:
chloride, metoprolol tartrate, pindolol, atenolol. distribution pH 7.0 pH 7.0 pH 7.4
timolol maleate. Drue coefficients and 20 "C and 37 "C and 37 'C
The n-octanol was washed with water and 1 M sodium Atenolol - 0.003 0.008
Nadolol - 0.008 0.022
hydroxide solution and then washed 3 times with Sotalol 0.01 1 0.01 1 0.012
Pindolol 0.12 0.20 0.29
distilled water. Acebutolol 0.62 (pH 7.4) 0.17 0.35
The phosphate buffers 0.1 M, pH 7.0 and pH 7.4 were Metoprolol 0.18 0.15 0.37
Tirnolol - 0.28 0.51
prepared from sodium dihydrogen orthophosphate and Oxprenolol 0.43 0.51 1.01
Labetalol - 4.6 8.3
di-sodium hydrogen orthophosphate. Propranolol 5.4 5.4 8.6
Correspondence. Coornbs et al 1980; Hellenbrecbt et a1 1973; Appelgren et al 1974.

CATIONS 173
It is apparent that these drugs fall into three groups 1976). The high protein binding of the lipophilic
with regard t o their distribution coefficients. blockers is an additional theoretical adverse factor in
Propranolol and labetalol are highly lipophilic, nadolol, terms of a predictable response since small changes in
sotalol and atenolol are lipophobic, the remaining plasma proteins, during for instance, illness, could
compounds being intermediate in the range. The highly significantly affect the concentrations of free drug in
lipophilic drugs had distribution coefficients up the blood. Recently, it has been suggested that blood
to 2 000 times those of the least lipid soluble drugs. concentrations of highly protein bound 8-blockers may
Generally. the 37 "C figure is approximately double be altered in inflammatory disease (Bishop et al 1980)
the room temperature result and it can be concluded and that increased plasma propranolol binding can
that temperature can significantly affect the distri- occur in myocardial infarction (Routledge et al 1980).
bution coefficients of the drugs. It has previously Ideally, the pharmacokinetic profile of a 8-blocker
been shown that small changes in pH result in large should comprise of long plasma half-life, no metabolism.
changes in distribution coefficients (Hellenbrecht 1973). low protein binding and low c.n.s. penetration. A low
Our results support this finding. Increasing the p H distribution coefficient is associated with these
from 7.0 to 7.4 generally caused up t o a threefold favourable pharmacokinetics. We have been able to
difference in the distribution coefficient. For most classify 8-blockers according to their lipophilicity and
compounds our results at room temperature, pH 7, have established that three drugs, nadolol, atenolol and
corresvond well with urevious workers. Differences can sotalol are much less lipophilic than the other seven
be explained by variations in experimental parameters, tested.
particularly temperature and pH. We have carefully We gratefully acknowledge the gifts of drug sub-
standardized temperature, pH and experimental stances from: Ciba Laboratories (oxprenolol hydro-
procedure to establish comparative liposolubilities. chloride). Bristol-Myers Ltd (sotalol hydrochloride),
The blood-brain barrier acts like a lipid membrane May and Baker Ltd (acebutolol hydrochloride). Astra
(Mayer et al 1959) and lipid-soluble drugs penetrate Chemicals Ltd (metoprolol tartrate), Sandoz Products
the central nervous system to a greater extent than Ltd (pindolol), I.C.I. Ltd (atenolol) and Merck, Sharp
water-soluble drugs. and Dohme Ltd (timolol).
Propranolol is highly concentrated in the brain, and
brain p l a s m ratios in the region of 15: 1 have been
demonstrated in animal and human studies (Myers et al
1975); less lipophilic drugs such as atenolol and
practolol penetrate the c.n.s. to a much lesser degree REFERENCES
(Day et al 1977). 8-Blockers are relatively free of Appelgren, C., Borg, K. O., Elofsson. R., Johansson,
troublesome side-effects, but c.n.s. effects can cause D. A. (1974) Acta Pharm. Sueclca. 11 : 325-332
problems in some patients (Fleminger 1978; Stephen Bishop. H., Kendall, M. J., Quarterman, C. P..
1966; Sanders 1978; Steinert & Pugh 1979). Clinically, Schneider, R. E. (1980) Br. J. Clin. Pharmacol. 9:
therefore, patients who have experienced adverse central 108P-109P
effects with propranolol or the other relatively lipo- Coombs, T. J., Coulson, C. J., Smith, V. I . (1980) Br. J.
philic /3-blockers might benefit by a change of therapy to Clin. Phannacol. 9: 395-397
a drug with a low lipophilicity. Double blind clinical Day, M. D., Hemsworth, B. A., Street, J. A. (1977) J.
Pharm. Pharmacol. 29: Suppl., 52P
comparisons of 8-blockers are required to confirm the Fleminger, R. (1978) Br. Med. J. 1: 1182
advantage of the lipophobic compounds in terms of Hellenbrecht. D., Lemmer, B., Wiethold, G.. Grobccker
central side effects. H. (1973) Nauny-Schmiedeberg's Arch. Pharmacol.
The Iiposolubility of &blockers is also correlated with 277: 21 1-226
the extent to which they are metabolized, highly Johnsson, G., Regardh, C.-G. (1976) Clin. Pharma-
lipophilic drugs such as propranolol being almost cokinet. 1: 233-263
completely metabolized and lipophobic drugs such as Kubinyi. H. (1979) Arzneim-Forsch. 29: 1067-1080
nadolol, sotalol and atenolol being little or completely Mayer, S. E., Maickel, R. P., Brodie, B. B. (1959) J.
unaffected by liver metabolism. A high degree of Pharmacol. 127: 205-21 1
metabolism during first pass through the liver has Myers. M. G., Lewis. P. J., Reid. J. L., Dollery, C. T.
(1975) J. Pharmacol. Exp. Ther. 192: 327-335
di~dvantages,since this introduces a variable which ~ d u t ~ e d ~P.e .A.. stargel, w.. w., Wagner. G. S.,
can affect plasma concentrations (Johnsson & Regardh Shand, D. G. (1980) Br. J. Chn. Pharmacol. 9: 438
1976). Sanders, G. L. (1978) Adv. Drug React. Bull. 68: 240
A high affinity for lipids also coincides with a high Steinert, J., Pugh, C. R. (1979) Br. Med. J. 1: 790
degree of plasma protein binding (Johnsson & Regardh Stephen, S. A. (1966) Am. J. Cardiol. 18: 463-472

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expected to have a higher incidence of sensitization and Bult, A., U. Uitterdijk, J. D., Klasen, H. B.

J. Pharm. Pharmacol. 1981, 33: 172-173 0022-3573181 1030172-02 $02.50/0

An investigation of the comparative liposolubilities of p-adrenoceptor

Correspondence. Coornbs et al 1980; Hellenbrecbt et a1 1973; Appelgren et al 1974.

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