Changes in pharmacokinetics of anti-HIV protease inhibitors during pregnancy: the role of CYP3A and P-glycoprotein.
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 CYP3A activity was detected and CYP3A protein expression (n = 6, p > 0.05) was not significantly different between the two groups. 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 its bioavailability. An increase in hepatic CYP3A can explain the reduced bioavailability of NFV during pregnancy. If such upregulation 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.
Mathias
Anita A
AA
Department of Pharmaceutics, University of Washington, Box 357610, Seattle, WA 98195, USA.
Maggio-Price
Lillian
L
Lai
Yurong
Y
Gupta
Anshul
A
Unadkat
Jashvant D
JD
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology*; D000818:Animals; D019540:Area Under Curve; D051544:Cytochrome P-450 CYP3A / Q000502:physiology*; D005260:Female; D017320:HIV Protease Inhibitors / Q000493:pharmacokinetics*; D051379:Mice; D019888:Nelfinavir / Q000493:pharmacokinetics*; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000378:metabolism*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D017320:HIV Protease Inhibitors; D051544:Cytochrome P-450 CYP3A; D019888:Nelfinavir