Abstract
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-199,331O-demethylation. Marked sex-related differences in plasma clearance (CLp) of CP-199,331 were observed in rats: 51 and 1.2 ml/min/kg in males and females, respectively. This difference in CLp was attributed to gender differences in metabolizing capacity because Vmax andKm 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 (CLh) of 64 and 2.5 ml/min/kg in male and female rats, respectively. These values were in close agreement with the in vivo CLp, suggesting that CP-199,331 CLp 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 thatO-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.
Footnotes
- Abbreviations used are::
- Cys-LT
- cysteinyl leukotriene
- CYP
- cytochrome P450
- CLp
- plasma clearance
- CLh
- hepatic clearance
- HPLC-UV
- high performance liquid chromatography-ultraviolet spectroscopy
- CL′int
- intrinsic clearance
- rCYP
- recombinant cytochrome P450
- LC/MS/MS
- liquid chromatography/mass spectrometry/mass spectrometry
- Rt
- retention time
- Received May 9, 2001.
- Accepted July 17, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|