Michael Z. Liao , Pharmaceutics, University of Washington, Seattle, WA
Linda Risler , Pharmaceutics, University of Washington, Seattle, WA
Brian Phillips , Pharmaceutics, University of Washington, Seattle, WA
Danny D. Shen , Pharmaceutics, University of Washington, Seattle, WA
Qingcheng Mao , Pharmaceutics, University of Washington, Seattle, WA
Recent statistics indicate that ~5% of pregnant women in the US report illicit drug use, posing major risks for maternal morbidities and neonatal complications [1]. Buprenorphine is commonly used to treat opiate addiction during pregnancy. Norbuprenorphine is the major active metabolite of buprenorphine in rodents and humans. Previous studies showed that norbuprenorphine, but not buprenorphine, is a P-gp substrate and a possible BCRP substrate. Norbuprenorphine is also a potent agonist for opioid receptors, causing respiratory depression in mice and children [2, 3]; however, little is known about the mechanism that controls its brain and fetal exposure. This is of concern because fetal exposure to norbuprenorphine may pose a significant risk to the fetuses. P-gp and BCRP are two major efflux transporters regulating drug distribution in tissues. In this study, we systematically analyzed the role of P-gp and BCRP in determining maternal brain and fetal distribution of norbuprenorphine in a pregnant mouse model. We administered 1 mg/kg of norbuprenorphine intravenously to pregnant FVB wild-type, Mdr1a-/-/b-/-, and Mdr1a-/-/b-/-/Bcrp1-/- mice on gestation day 15. Maternal plasma, maternal brain tissues, and fetuses were collected at various time points after administration and quantified by a validated LC-MS assay. The maternal plasma AUC of norbuprenorphine in Mdr1a-/-/b-/- and Mdr1a-/-/b-/-/Bcrp1-/- mice were comparable; both were ~2-fold greater than that in wild-type. Fetal AUC was also increased in Mdr1a-/-/b-/- and Mdr1a-/-/b-/-/Bcrp1-/- mice compared to wild-type mice. However, the fetal-to-maternal plasma AUC ratio (~0.5) was not affected by the knockout of Mdr1 or Bcrp1. Moreover, the maternal brain-to-maternal plasma AUC ratio in wild-type mice (~0.13) was increased ~20-fold compared to that (~2.5) in Mdr1a-/-/b-/- or Mdr1a-/-/b-/-/Bcrp1-/- mice. In conclusion, we showed that the knockout of P-gp increased systemic exposure of norbuprenorphine in pregnant mice, suggesting P-gp plays an important role in systemic clearance of norbuprenorphine. Fetal exposure to norbuprenorphine was substantial, ~50% of maternal plasma exposure. Although fetal exposure was also increased by the knockout of P-gp, the fetal/maternal plasma AUC ratio did not change, suggesting that P-gp plays a minor role in limiting norbuprenorphine fetal exposure. In contrast, the knockout of P-gp drastically increased brain exposure, indicating a significant role of P-gp in reducing brain distribution of norbuprenorphine. This demonstrates the differential roles of a transporter in determining drug distribution into different types of tissues in a mouse model. The results also suggest that the blood-placental barrier is more penetrable by norbuprenorphine than the blood-brain barrier. Finally, since the data were similar in Mdr1a-/-/b-/- and Mdr1a-/-/b-/-/Bcrp1-/-mice, we conclude that Bcrp1 is not as important as P-gp in determining both the systemic and tissue exposure to norbuprenorphine.

1. Marwick C: Challenging report on pregnancy and drug abuse. Jama 1998, 280:1039-1040.

2. Kim HK, Smiddy M, Hoffman RS, Nelson LS: Buprenorphine may not be as safe as you think: a pediatric fatality from unintentional exposure. Pediatrics 2012, 130:e1700-1703.

3. Brown SM, Campbell SD, Crafford A, Regina KJ, Holtzman MJ, Kharasch ED: P-glycoprotein is a major determinant of norbuprenorphine brain exposure and antinociception. J Pharmacol Exp Ther 2012, 343:53-61.