睾酮抑制对一种强效促性腺激素释放激素（GnRH）受体拮抗剂药代动力学的影响。

Effect of testosterone suppression on the pharmacokinetics of a potent gnRH receptor antagonist.

作者信息

Iatsimirskaia Eugenia A, Gregory Margaret L, Anderes Kenna L, Castillo Rosemary, Milgram K Eric, Luthin David R, Pathak Ved P, Christie Lance C, Vazir Haresh, Anderson Mark B, May John M

机构信息

Department of Pharmacokinetics, Dynamics & Metabolism, Pfizer Global Research & Development/Agouron Pharmaceuticals, Inc, San Diego, California 92121, USA.

出版信息

Pharm Res. 2002 Feb;19(2):202-8. doi: 10.1023/a:1014281018271.

DOI:10.1023/a:1014281018271

PMID:11883648

Abstract

PURPOSE

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.

摘要

目的

细胞色素P450酶（CYPs）在动物和人类中的表达受复杂的激素调节。长期使用改变性激素水平的药物（如GnRH受体激动剂或拮抗剂）可能会影响激素依赖性CYPs的表达，进而影响由它们代谢的药物的药代动力学。

方法

通过将AG - 045572（0.1 - 30 microM）与人或大鼠肝微粒体、或表达的CYP3A4和CYP3A5孵育来获得酶动力学参数。在完整雄性、雌性、去势雄性大鼠以及用AG - 045572预处理4天的雄性大鼠中研究AG - 045572（静脉注射10 mg/kg或口服20 mg/kg）的药代动力学。

结果

AG - 045572在大鼠和人类中均由CYP3A代谢。男性和女性人类、雌性大鼠肝微粒体以及表达的CYP3A4和CYP3A5中的Km值相似（分别为0.39、0.27、0.28、0.25和0.26 microM）。雄性大鼠肝微粒体中的Km为1.5 microM，表明在雄性和雌性大鼠中AG - 045572由不同的CYP3A同工酶代谢。AG - 045572在完整雄性大鼠中的口服生物利用度为8%，而在雌性或去势雄性大鼠中为24%。对完整雄性大鼠肌肉注射AG - 045572预处理4天导致睾酮抑制至去势水平，同时AG - 045572的口服生物利用度增加至27%。在同一实验中，生长激素的雄性特异性脉冲模式保持不变，基线水平略有升高。