Vol. 29, Issue 11, 1403-1409, November 2001

Pharmacokinetics and Metabolism of a Cysteinyl Leukotriene-1 Receptor Antagonist from the Heterocyclic Chromanol Series in Rats: In Vitro-In Vivo Correlation, Gender-Related Differences, Isoform Identification, and Comparison with Metabolism in Human Hepatic Tissue

Alexander V. Kuperman, Amit S. Kalgutkar, Anthony Marfat, Robert J. Chambers, and Theodore E. Liston

Departments of Pharmacokinetics, Dynamics, and Metabolism (A.V.K., A.S.K.), Candidate Enhancement (T.E.L.), and Chemistry (A.M., R.J.M.), Pfizer Global Research and Development, Groton, Connecticut

CP-199,331 is a potent antagonist of the cysteinyl leukotriene-1 (LT₁) receptor, targeted for the treatment of asthma. The pharmacokinetic/metabolism properties of CP-199,331 were studied in rats and compared with those in human liver microsomes/hepatocytes. In vitro biotransformation of CP-199,331 in rat and human hepatocytes was similar, consisting primarily of CP-199,331 O-demethylation. Marked sex-related differences in plasma clearance (CL_p) of CP-199,331 were observed in rats: 51 and 1.2 ml/min/kg in males and females, respectively. This difference in CL_p was attributed to gender differences in metabolizing capacity because V_max and K_m values for CP-199,331 metabolism were 30-fold higher and 8-fold lower, respectively, in male rat liver microsomes compared with female microsomes. Scale-up of the in vitro microsomal data predicted hepatic clearance (CL_h) of 64 and 2.5 ml/min/kg in male and female rats, respectively. These values were in close agreement with the in vivo CL_p, suggesting that CP-199,331 CL_p in male and female rats was entirely due to hepatic metabolism. Studies with rat recombinant cytochromes P450 and anti-rat cytochrome P450 (CYP) antibodies revealed the involvement of male rat-specific CYP2C11 in the metabolism of CP-199,331. In contrast, CP-199,331 metabolism in human liver microsomes was principally mediated by CYP3A4. The projected human clearance in liver microsomes and hepatocytes varied 6-fold from low to moderate, depending on CYP3A4 activity. Considering that O-demethylation is the major route of elimination in humans, the in vivo clearance of CP-199,331 may exhibit moderate variability, depending on CYP3A4 abundance in the human population.