Diphenhydramine active uptake at the blood-brain barrier and its interaction with oxycodone in vitro and in vivo

Muhammad Waqas Sadiq, Annika Borgs, Takashi Okura, Keita Shimomura, Sayaka Kato, Yoshiharu Deguchi, Britt Jansson, Sven Björkman, Tetsuya Terasaki, Margareta Hammarlund-udenaes

研究成果: Article査読

63 被引用数 (Scopus)

抄録

Diphenhydramine (DPHM) and oxycodone are weak bases that are able to form cations. Both drugs show active uptake at the blood-brain barrier (BBB). There is thus a possibility for a pharmacokinetic interaction between them by competition for the same uptake transport system. The experiments of the present study were designed to study the transport of DPHM across the BBB and its interaction with oxycodone in vitro and in vivo. In vitro, the interaction between the drugs was studied using conditionally immortalized rat brain capillary endothelial cells (TR-BBB13 cells). The in vivo relevance of the in vitro findings was studied in rats using brain and blood microdialysis. DPHM was actively transported across the BBB in vitro (TR-BBB13 cells). Oxycodone competitively inhibited DPHM uptake with a Ki value of 106μM. DPHM also competitively inhibited oxycodone uptake with a Ki value of 34.7μM. In rats, DPHM showed fivefold higher unbound concentration in brain interstitial fluid (ISF) than in blood, confirming a net active uptake. There was no significant interaction between DPHM and oxycodone in vivo. This accords with the results of the in vitro experiments because the unbound plasma concentrations that could be attained in vivo, without causing adverse effects, were far below the Ki values.

本文言語English
ページ(範囲)3912-3923
ページ数12
ジャーナルJournal of Pharmaceutical Sciences
100
9
DOI
出版ステータスPublished - 2011 9

ASJC Scopus subject areas

  • 薬科学

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