Distribution of Saquinavir, Methadone, and Buprenorphine in Maternal Brain, Placenta, and Fetus During Two Different Gestational Stages of Pregnancy in Mice

Efflux transporters such as P-glycoprotein (P-gp) play a critical role in the maternal-to-fetal and blood-to-brain transfer of many drugs. Using a mouse model, the effects of gestational age on P-gp and MRP expression in the placenta and brain were evaluated. P-gp protein levels in the placenta and brain were greater at mid-gestation (gd 13) than late-gestation (gd 18). Likewise, brain MRP1 levels were greater at mid-gestation, whereas, placental levels were greater at late-gestation. To evaluate these effects on drug disposition, concentrations of [H-3]saquinavir, [H-3]methadone, [H-3]buprenorphine, and the paracellular marker, [C-14]mannitol were measured in plasma, brain, placenta, and fetal samples after i.v. administrations to nonpregnant and pregnant mice. Following i.v. administration, [H-3]saquinavir placenta-to-plasma and fetal-to-plasma ratios were significantly greater in late-gestation mice versus mid-gestation. Furthermore, late-gestation mice experienced significant increases in the [H-3]saquinavir and [H-3]methadone brain-to-plasma ratios 60 min after dosing relative to mid-gestation (p<0.05). No significant differences were observed in these tissue-to-plasma ratios for buprenorphine or mannitol. Repeated dosing (three doses, once daily) decreased the differential uptake of [H-3]saquinavir in brain but potentiated it in the fetus. These results suggest that differential expression of P-gp and possibly MRP1 contributes to the gestational-induced changes in brain and fetal uptake of saquinavir. (C) 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:2832-2846, 2009