Received for publication September 9, 2005.
Revised November 3, 2005.
Accepted for publication November 7, 2005.

CHANGES IN PHARMACOKINETICS OF ANTI-HIV PROTEASE INHIBITORS DURING PREGNANCY: THE ROLE OF CYP3A AND P-GLYCOPROTEIN

Abstract

HIV-infected women have reduced exposure (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 IV 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 non-pregnant 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 non-pregnant mice (n=7). Hepatic CYP3A activity (testosterone 6-hydroxylation, n=4) and expression (n=8) was significantly higher (by 138% and 49%, p< 0.05) in pregnant mice than that in non-pregnant mice. In the intestine, no CYP3A activity was detected and CYP3A protein expression (n=6, p>0.05) was not significantly different between the two groups. P-gp expression (n=6) in hepatic and intestinal tissue of pregnant mice was not significantly different from that in non-pregnant mice. These changes in disposition of NFV during pregnancy are predominately due to a change in its bioavailability. Increase in hepatic CYP3A can explain the reduced bioavailability of NFV during pregnancy. If such up-regulation of hepatic CYP3A activity occurs in pregnant women, it has important implications for dose adjustment of a variety of drugs ingested by pregnant women and cleared predominately via CYP3A metabolism.

Key words: CYP3A metabolism, P-glycoprotein, mouse, nelfinavir, pharmacokinetics, pregnancy

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