title: Drug-drug interaction between oxycodone and adjuvant analgesics in blood-brain barrier transport and antinociceptive effect.
abstract: To examine possible blood-brain barrier (BBB) transport interactions between oxycodone and adjuvant analgesics, we firstly screened various candidates in vitro using [(3)H]pyrilamine, a substrate of the oxycodone transporter, as a probe drug. The uptake of [(3)H]pyrilamine by conditionally immortalized rat brain capillary endothelial cells (TR-BBB13) was inhibited by antidepressants (amitriptyline, imipramine, clomipramine, amoxapine, and fluvoxamine), antiarrhythmics (mexiletine, lidocaine, and flecainide), and ketamine. On the other hand, antiepileptics (carbamazepine, phenytoin, and clonazepam) and corticosteroids (dexamethasone and prednisolone) did not inhibit [(3)H]pyrilamine uptake, with the exception of sodium valproate. The uptake of oxycodone was significantly inhibited in a concentration-dependent manner by amitriptyline, fluvoxamine and mexiletine with K(i) values of 13, 65, and 44 microM, respectively. These K(i) values are 5-300 times greater than the human therapeutic plasma concentrations. Finally, we evaluated in vivo interaction between oxycodone and amitriptyline in mice. Antinociceptive effects of oxycodone were increased by coadministration of amitriptyline. The oxycodone concentrations in plasma and brain were not changed by coadministration of amitriptyline. Overall, the results suggest that several adjuvant analgesics may interact with the BBB transport of oxycodone at relatively high concentrations. However, it is unlikely that there would be any significant interaction at therapeutically or pharmacologically relevant concentrations.
authors.affiliation: Department of Drug Disposition & Pharmacokinetics, School of Pharmaceutical Sciences, Teikyo University, 1091-1 Suarashi, Sagamiko, Sagamihara, Kanagawa 229-0195, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakazawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Okura
authors.forename: Keita
authors.initials: K
authors.lastname: Shimomura
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Terasaki
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Deguchi
mesh_terms: D000277:Adjuvants, Pharmaceutic / Q000493:pharmacokinetics / Q000494:pharmacology*; D000700:Analgesics / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010098:Oxycodone / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D010146:Pain / Q000188:drug therapy; D010147:Pain Measurement; D051381:Rats; D013997:Time Factors
chemical_list: D000277:Adjuvants, Pharmaceutic; D000700:Analgesics; D000701:Analgesics, Opioid; D010098:Oxycodone