PHARMACOKINETIC DISPOSITION OF GUANABENZ IN THE RHESUS-MONKEY

  • 1 January 1981
    • journal article
    • research article
    • Vol. 9  (6) , 509-514
Abstract
The pharmacokinetics of guanabenz (E-2,6-dichlorobenzylidene aminoguanidine acetate, Wy-8678) [an antihypertensive agent] 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/kg, as indicated by tissue and urinary recovery of the label. Excretion into urine accounted for 57 .+-. 3 of the radioactive ig dose. Recovery of radioactivity in urine after i.v. 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 i.v. and ig doses were fitted by polyexponential equations with a terminal elimination half-life of 12.0 .+-. 1.1 h. A large distribution volume .**GRAPHIC**. = 10.3 .+-. 0.7 l/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 per 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 curves (AUC) of 1 and 5 mg/kg ig doses. The low systemic availability of 0.19-0.31 reflects the extensive presystemic extraction (1st-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.