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.
Bibliographical noteFunding Information:
This work was supported by the National Institute on Drug Abuse (Award No. F310A022816). The content is solely the responsibility of the authors and does not necessarily represent the official views of NIDA or the NIH.
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- ABC transporters
- Blood-brain barrier