Pharmacokinetics of β-adrenoceptor blockers in obese and normal volunteers

Abstract

Aims Obesity can modify the pharmacokinetics of lipophilic drugs. As β-adrenoceptor blockers (BB) are often prescribed for obese patients suffering from hypertension or coronary heart disease, this study compares the pharmacokinetics of lipophilic β-adrenoceptor blockers in obese and control subjects.

Methods Nine obese (157±24% of ideal body weight (IBW) mean±s.d.) and nine non-obese healthy volunteers (98±10% IBW), aged 32±9 years, were included in the study. Subjects were randomly given a single i.v. infusion of one of the following racemic β-adrenoceptor blockers, whose doses (expressed as base per kg of IBW) were: propranolol (0.108 mg), labetalol (0.99 mg) and nebivolol (0.073 mg). The plasma concentrations of unchanged drugs were measured by h.p.l.c. The ionisation constants and lipophilicity parameters of β-adrenoceptor blockers were assessed.

Results The pharmacokinetic data for the three drugs were qualitatively similar. There was 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 β-adrenoceptor was studied by combining the current results with those previously obtained with a moderately lipophilic drug (bisoprolol) and a hydrophilic one (sotalol). The V_ss of the five drugs was positively and well-correlated (r²=0.90; P<0.01) with their distribution coefficient at pH 7.4 (log D^7.4 ), but not with their partition coefficients. The linear regression coefficients for lean and obese subjects were very similar.

Conclusions Lipophilic β-adrenoceptor blockers seem to diffuse less into adipose than into lean tissues. All electrical forms of the drugs (i.e. cations, neutral forms, or zwitterions) present at physiological pH contribute to their tissue distribution, in both obese and lean subjects.Their tissue distribution in obese patients could be restricted by the sum of hydrophobic forces and hydrogen bonds they elicit with macromolecules in lean tissues.

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