PHARMACOKINETICS OF BETA-ADRENOCEPTOR BLOCKERS IN OBESE AND NORMAL VOLUNTEERS

Aims Obesity can modify the pharmacokinetics of lipophilic drugs. As b eta-adrenoceptor blockers (BB) are often prescribed for obese patients suffering h-om hypertension or coronary heart disease, this study com pares the pharmacokinetics of lipophilic beta-adrenoceptor blockers in obese and control subjects. Methods Nine obese (157 +/- 24% of idea b ody weight (IBW) mean +/- s.d.) and nine non-obese healthy volunteers (98 +/- 30% LEW), aged 32 +/- 9 years, were included in the study. Sub jects were randomly given a single i.v. infusion of one of the followi ng racemic beta-adrenoceptor blockers, whose doses (expressed as base per kg of IBW) were: propranolol (0.108 mg), labetalol (0.99 mg) and n ebivolol (0.073 mg). The plasma concentrations of unchanged drugs were measured by h.p.l.c. The ionisation constants and lipophilicity param eters of beta-adrenoceptor blockers were assessed. Results The pharmac okinetic data for the three drugs were qualitatively similar. There wa s a trend towards a greater total distribution volume (V-ss) in obese patients than in controls. However, V-ss expressed per kg body weight was slightly smaller in obese patients. The relationship between V-ss and lipophilicity of five beta-adrenoceptor was studied by combining t he current results with those previously obtained with a moderately li pophilic drug (bisoprolol) and a hydrophilic one (sotalol). The V-ss o f the five drugs was positively and well-correlated (r(2) = 0.90; P < 0.01) with their distribution coefficient at pH 7.4 (log D-7.4), but n ot with their partition coefficients. The linear regression coefficien ts for lean and obese subjects were very similar. Conclusions Lipophil ic beta-adrenoceptor blockers seem to diffuse less into adipose than i nto lean tissues. All electrical forms of the drugs (i.e. cations, neu tral forms, or zwitterions) present at physiological pH contribute to their tissue distribution, in both obese and lean subjects. Their tiss ue distribution in obese patients could be restricted by the sum of hy drophobic forces and hydrogen bonds they elicit with macromolecules in lean tissues.