COMPARATIVE BIOAVAILABILITY AND PHARMACOKINETIC STUDIES OF AZATHIOPRINE AND 6-MERCAPTOPURINE IN THE RHESUS-MONKEY

Abstract

Azathioprine (AZA) [an immunosuppressive agent] is cleaved in vivo by glutathione to 6-mercaptopurine (6-MP). 6-MP plasma levels were measured by HPLC [high pressure liquid chromatography] in 4 male rhesus monkeys following oral and i.v. doses of the 2 drugs. Following i.v. 6-MP administration, 6-MP levels were described by a 2-compartment body model; mean terminal half-life, plasma clearance (CLp) and volume of distribution (Vdss) were 41.6 .+-. 12.1 min, 48.4 .+-. 15.4 ml/min per kg and 1.76 .+-. 0.64 l/kg, respectively. 8-Hydroxymercaptopurine (8-OHMP) was identified as a metabolite of AZA. 8-OHMP had a CLp twice that for 6-MP, while its Vdss was similar to that for 6-MP. After an i.v. dose, AZA was converted to 6-MP to the extent of 15%. The conversion of AZA to 6-MP and 8-OHMP was independent of the route of administration. Differences in AZA and 6-MP kinetics among the monkeys were attributed to differences in individual aldehyde oxidase and xanthine oxidase levels.