Sexual dimorphism in phencyclidine in vitro metabolism and pharmacokinetics in rats

Studies were conducted to determine the differences in phencyclicline (PCP) in vitro metabolism and pharmacokinetics in female and male Sprague-Dawley (SD) rats. Formation rates of five major PCP metabolites in liver microsom es weve significantly higher (p < .05) in males compared with females in th ree different vat strains (SD, Fischer 344, and Dark Agouti). In addition, the formation rate for an irreversibly bound PCP metabolite in males was th e second highest of the six metabolites measured in these studies. However, the liver microsomes from the females produced essentially no metabolite b inding in any strain. To determine the in vivo consequences of these in vit ro metabolism results, we determined PCP's pharmacokinetic profile in femal e SD rats after a pharmacologically active i.v. dose of PCP (1 mg/kg) and t hen compared these data with the pharmacokinetic profile in male SD rats. T he value for PCP systemic (and nonrenal) clearance was more than 45% lower (p < .05) in female rats. In addition, the terminal elimination T-1/2 was s ignificantly longer (p < .05) in the female rats (5.5 versus 3.4 h, respect ively). Because the initial serum concentration, volume of distribution at steady state, and renal clearance were not significantly different between the sexes, the longer half-life was attributed directly to a decreased abil ity of females to metabolize the drug. Consequently, these pharmacokinetic data suggest pharmacological differences in PCP effects between female and male rats are due primarily to a decreased ability of female rats to metabo lize the drug.