Changes in Pharmacokinetics of Anti-HIV Protease Inhibitors during Pregnancy:The Role of CYP3A and P-glycoprotein

摘要

Human immunodeficiency virus (HIV)-infected women have reduced exposure [area under the curve (AUC)] to anti-HIV protease inhibitors [e.g.,nelfinavir (NFV)] during pregnancy.To determine the mechanistic basis of this phenomenon,we administered NFV mesylate orally (2.5 mg) or intravenously (0.625 mg) to timed pregnant (gestational age:18-19 days) and non-pregnant FVB mice.After oral but not after i.v.administration,the plasma clearance of NFV was higher (by 134%,p < 0.05) and bioavailability was lower (by 32%,p < 0.05) in pregnant (n = 3) versus nonpregnant mice (n = 3).These effects of pregnancy were not due to changes in plasma protein binding of NFV.The half-life of NFV depletion in hepatic S-9 fractions of pregnant mice (n = 8) was 2.2-fold faster (p < 0.05) than that in nonpregnant mice (n = 7).Hepatic CYP3A activity (testosterone 6beta-hydroxylation,n = 4) and expression (n = 8) were significantly higher (by 138 and 49%,p < 0.05) in pregnant mice than that in nonpregnant mice.In the intestine,no CYP3Aactivity was detected and CYP3A protein expression (n = 6,p > 0.05) was not significantly different between the twogroups.P-glycoprotein expression (n = 6) in hepatic and intestinal tissue of pregnant mice was not significantly different from that in nonpregnant mice.These changes in disposition of NFV during pregnancy are predominately due to a change in itsbioavailability.An increase in hepatic CYP3A can explain thereduced bioavailability of NFV during pregnancy.If such up-regulation of hepatic CYP3A activity occurs in pregnantwomen,it has important implications for dose adjustment of avariety of drugs ingested by pregnant women and clearedpredominately via CYP3A metabolism.