Effect of testosterone suppression on the pharmacokinetics of a potent gnRH receptor antagonist.
OBJECTIVE
The expression of cytochrome P450 enzymes (CYPs) in animals and humans is under complex hormonal regulation. Chronic treatment with drugs that alter sex hormone levels such as GnRH receptor agonists or antagonists may affect the expression of hormone-dependent CYPs, and as a result the pharmacokinetics of drugs metabolized by them.


METHODS
Enzyme kinetic parameters were obtained by incubating AG-045572 (0.1-30 microM) with human or rat liver microsomes, or expressed CYP3A4 and CYP3A5. The pharmacokinetics of AG-045572 (10 mg/kg i.v. or 20 mg/kg p.o.) were studied in intact male, female, castrated male and male rats pretreated with AG-045572 for 4 days.


RESULTS
AG-045572 is metabolized by CYP3A in both rats and humans. The Km values were similar in male and female human, female rat liver microsomes, and expressed CYP3A4 and CYP3A5 (0.39, 0.27, 0.28, 0.25, and 0.26 microM, respectively). The Km in male rat liver microsomes was 1.5 microM, suggesting that in male and female rats AG-045572 is metabolized by different CYP3A isozymes. The oral bioavailability of AG-045572 in intact male rats was 8%, while in female or castrated male rats it was 24%. Pretreatment of intact male rats with AG-045572 i.m. for 4 days resulted in suppression of testosterone to castrate levels, accompanied by an increase in oral bioavailability of AG-045572 to 27%. In the same experiment, the male-specific pulsatile pattern of growth hormone remained unchanged with slightly elevated baseline levels.


CONCLUSIONS
The potent GnRH receptor antagonist AG-045572 is metabolized by hormone-dependent CYP3A. As a result, suppression of testosterone by pretreatment with AG-045572 "feminized" its own pharmacokinetics.
Iatsimirskaia
Eugenia A
EA
Department of Pharmacokinetics, Dynamics & Metabolism, Pfizer Global Research & Development/Agouron Pharmaceuticals, Inc, San Diego, California 92121, USA. eugenia.iatsimirskai@agouron.com
Gregory
Margaret L
ML
Anderes
Kenna L
KL
Castillo
Rosemary
R
Milgram
K Eric
KE
Luthin
David R
DR
Pathak
Ved P
VP
Christie
Lance C
LC
Vazir
Haresh
H
Anderson
Mark B
MB
May
John M
JM
D000465:Algorithms; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D005260:Female; D005663:Furans / Q000494:pharmacology*; D013006:Growth Hormone / Q000097:blood; D006727:Hormone Antagonists / Q000493:pharmacokinetics*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D011966:Receptors, LHRH / Q000037:antagonists & inhibitors*; D013739:Testosterone / Q000037:antagonists & inhibitors* / Q000097:blood; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*
C464763:AG045572; D065607:Cytochrome P-450 Enzyme Inhibitors; D005663:Furans; D006727:Hormone Antagonists; D011966:Receptors, LHRH; D013764:Tetrahydronaphthalenes; D013739:Testosterone; D013006:Growth Hormone; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating