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 [(3)H]saquinavir, [(3)H]methadone, [(3)H]buprenorphine, and the paracellular marker, [(14)C]mannitol were measured in plasma, brain, placenta, and fetal samples after i.v. administrations to nonpregnant and pregnant mice. Following i.v. administration, [(3)H]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 [(3)H]saquinavir and [(3)H]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 [(3)H]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.
Coles
Lisa D
LD
Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, 20 Penn Street, Baltimore, Maryland, USA.
Lee
Insong J
IJ
Hassan
Hazem E
HE
Eddington
Natalie D
ND
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002047:Buprenorphine / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D047109:Fetal Development / Q000187:drug effects / Q000502:physiology; D005333:Fetus / Q000187:drug effects / Q000378:metabolism; D018811:Maternal Exposure; D008431:Maternal-Fetal Exchange / Q000187:drug effects / Q000502:physiology; D008691:Methadone / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D010920:Placenta / Q000187:drug effects / Q000378:metabolism*; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000187:drug effects / Q000378:metabolism*; D019258:Saquinavir / Q000378:metabolism* / Q000494:pharmacology; D014018:Tissue Distribution / Q000187:drug effects / Q000502:physiology
D002047:Buprenorphine; D019258:Saquinavir; D008691:Methadone