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 [³H]saquinavir, [³H]methadone, [ ³H]buprenorphine, and the paracellular marker, [¹⁴C] mannitol were measured in plasma, brain, placenta, and fetal samples after i.v. administrations to nonpregnant and pregnant mice. Following i.v. administration, [³H]saquinavir placenta-to-plasma and fetal-to-plasma ratios were significantly greater in lategestation mice versus mid-gestation. Furthermore, late-gestation mice experienced significant increases in the [ ³H]saquinavir and [³H]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 [³H]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.