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.

Abstract

CP-199,331 is a potent antagonist of the cysteinyl leukotriene-1 (LT(1)) 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.

• Authors: A V Kuperman, A S Kalgutkar, A Marfat, R J Chambers, T E Liston
• Journal: Drug metabolism and disposition: the biological fate of chemicals (Drug Metab Dispos) Vol. 29 Issue 11 Pg. 1403-9 (Nov 2001) ISSN: 0090-9556 [Print] United States
• PMID: 11602515 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Antioxidants
• Benzopyrans
• CP 199331
• Chromans
• Heterocyclic Compounds
• Isoenzymes
• Leukotriene Antagonists
• Membrane Proteins
• Receptors, Leukotriene
• Sulfonamides
• Cytochrome P-450 Enzyme System
• 2,2,5,7,8-pentamethyl-1-hydroxychroman
• cysteinyl leukotriene receptor 2
• leukotriene D4 receptor

Topics

• Animals
• Antioxidants (administration & dosage, chemistry, pharmacokinetics)
• Benzopyrans (administration & dosage, chemistry, pharmacokinetics)
• Biotransformation
• Chromans (administration & dosage, chemistry, pharmacokinetics)
• Cytochrome P-450 Enzyme System (metabolism)
• Female
• Hepatocytes (cytology, enzymology, metabolism)
• Heterocyclic Compounds (administration & dosage, chemistry, pharmacokinetics)
• Humans
• Injections, Intravenous
• Isoenzymes (metabolism)
• Leukotriene Antagonists
• Male
• Membrane Proteins
• Microsomes, Liver (enzymology, metabolism)
• Rats
• Rats, Sprague-Dawley
• Receptors, Leukotriene
• Sex Characteristics
• Sulfonamides (administration & dosage, chemistry, pharmacokinetics)