Opiates inhibit paclitaxel uptake by P-glycoprotein in preparations of human placental inside-out vesicles

Sarah J. Hemauer, Svetlana L. Patrikeeva, Tatiana N. Nanovskaya, Gary D.V. Hankins, Mahmoud S. Ahmed

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

The use of either methadone or buprenorphine for treatment of the pregnant opiate-dependent patient improves maternal and neonatal outcome. However, patient outcomes are often complicated by neonatal abstinence syndrome (NAS). The incidence and severity of NAS should depend on opiate concentration in the fetal circulation. Efflux transporters expressed in human placental brush border membranes decrease fetal exposure to medications by their extrusion to the maternal circulation. Accordingly, the concentration of either methadone or buprenorphine in the fetal circulation is, in part, dependent on the activity of the efflux transporters. The objective of this study was to characterize the activity of P-gp and its interaction with opiates in the placental apical membrane. Therefore, brush border membrane vesicles were prepared from human placenta. The vesicles were oriented approximately 75% inside-out, exhibited saturable ATP-dependent uptake of P-gp substrate [3H]-paclitaxel with an apparent Kt of 66 ± 38 nM and Vmax of 20 ± 3 pmol mg protein-1 min-1. Methadone, buprenorphine, and morphine inhibited paclitaxel transport with apparent Ki of 18, 44, and 90 μM, respectively. Our data indicate that a method has been established to determine the activity of the efflux transporter P-gp, expressed in placental brush border membranes, and the kinetics for the transfer of its prototypic substrate paclitaxel. Furthermore, the method was used to determine the effects of methadone, buprenorphine, and morphine on paclitaxel transfer by placental P-gp and revealed that they have higher affinity to the transporter than its classical inhibitor verapamil (Ki, 300 μM).

Original languageEnglish (US)
Pages (from-to)1272-1278
Number of pages7
JournalBiochemical Pharmacology
Volume78
Issue number9
DOIs
StatePublished - Nov 1 2009

Keywords

  • Buprenorphine
  • Membrane vesicle
  • Methadone
  • P-glycoprotein
  • Placenta

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

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