Pharmacokinetic disposition of guanabenz in the rhesus monkey

The pharmacokinetics of guanabenz (E-2,6-dichlorobenzylidene aminoguanidine acetate, Wy-8678) in rhesus monkeys given ¹⁴C-labeled and unlabeled drug were investigated. The radioactive dose was well absorbed after intragastric (ig) administration of 1 mg of the labeled drug per kg, as indicated by tissue and urinary recovery of the label. Excretion into urine accounted for 57 ± 3 (SE)% of the radioactive ig dose. Recovery of radioactivity in urine after iv administration of 0.2 mg/kg was 79 ± 0.6% of the radioactive dose. Less than 1% of the dose was recovered in urine as unchanged drug after either route of administration. Plasma concentration/time profiles after 1-mg/kg iv and ig doses were fitted by polyexponential equations with a terminal elimination half-life of 12.0 ± 1.1 hr. A large volume of distribution (V(ss)(D) = 10.3 ± 0.7 liters/kg) indicated extensive extravascular distribution of the drug, which was confirmed by ¹⁴C-distribution studies. The systemic clearance was 27.5 ± 1.4 ml/min/kg with hepatic clearance appearing to be the major determinant in guanabenz elimination. Dose proportionality was evident from a comparison of areas under the plasma concentration-time curve (AUC) of 1- and 5-mg/kg ig doses. The low systemic availability of 0.19-0.31 reflects the extensive presystemic extraction (first-pass effect) of the drug. Similarities in the pharmacokinetics of guanabenz in man and the rhesus monkey indicate that the latter species may serve as a satisfactory model for man in disposition studies.