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.
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.
Kuperman
A V
AV
Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Global Research and Development, Groton, CT 06340, USA. alexander_v_kuperman@groton.pfizer.com
Kalgutkar
A S
AS
Marfat
A
A
Chambers
R J
RJ
Liston
T E
TE
D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D001578:Benzopyrans / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D001711:Biotransformation; D002839:Chromans / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005260:Female; D022781:Hepatocytes / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D006571:Heterocyclic Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D006801:Humans; D007275:Injections, Intravenous; D007527:Isoenzymes / Q000378:metabolism; D020024:Leukotriene Antagonists; D008297:Male; D008565:Membrane Proteins; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018077:Receptors, Leukotriene; D012727:Sex Characteristics; D013449:Sulfonamides / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics
D000975:Antioxidants; D001578:Benzopyrans; C122099:CP 199331; D002839:Chromans; D006571:Heterocyclic Compounds; D007527:Isoenzymes; D020024:Leukotriene Antagonists; D008565:Membrane Proteins; D018077:Receptors, Leukotriene; D013449:Sulfonamides; D003577:Cytochrome P-450 Enzyme System; C029141:2,2,5,7,8-pentamethyl-1-hydroxychroman; C412375:cysteinyl leukotriene receptor 2; C083169:leukotriene D4 receptor