title: Diphenhydramine active uptake at the blood-brain barrier and its interaction with oxycodone in vitro and in vivo.
abstract: 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 K(i) value of 106 μM. DPHM also competitively inhibited oxycodone uptake with a K(i) value of 34.7 μM. 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 K(i) values.
authors.affiliation: Department of Pharmaceutical Biosciences, Uppsala University, SE-75124 Uppsala, Sweden.
authors.forename: Muhammad Waqas
authors.initials: MW
authors.lastname: Sadiq
authors.forename: Annika
authors.initials: A
authors.lastname: Borgs
authors.forename: Takashi
authors.initials: T
authors.lastname: Okura
authors.forename: Keita
authors.initials: K
authors.lastname: Shimomura
authors.forename: Sayaka
authors.initials: S
authors.lastname: Kato
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Deguchi
authors.forename: Britt
authors.initials: B
authors.lastname: Jansson
authors.forename: Sven
authors.initials: S
authors.lastname: Björkman
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Terasaki
authors.forename: Margareta
authors.initials: M
authors.lastname: Hammarlund-Udenaes
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier; D002461:Cell Line, Transformed; D002853:Chromatography, Liquid; D004155:Diphenhydramine / Q000493:pharmacokinetics* / Q000494:pharmacology; D004347:Drug Interactions; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D006634:Histamine H1 Antagonists / Q000493:pharmacokinetics* / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D013058:Mass Spectrometry; D010098:Oxycodone / Q000494:pharmacology*; D011786:Quality Control; D051381:Rats; D017207:Rats, Sprague-Dawley; D012015:Reference Standards
chemical_list: D006634:Histamine H1 Antagonists; D004155:Diphenhydramine; D010098:Oxycodone