Effect of hydrocotarnine on cytochrome P450 and P-glycoprotein.
The injectable form of oxycodone contains hydrocotarnine that is supposed to potentiate the analgesic effect of oxycodone with unknown mechanism(s). In this study, the effects of hydrocotarnine on the cytochrome P450 (CYP) and P-glycoprotein (P-gp) were investigated. Hydrocotarnine did not induce a significant change in the metabolic activities of CYP2C9, 2C19, and 2E1 in an in vitro study using human CYP recombinants. Although weak inhibitory effects were observed on CYP3A4 and 2D6, these interactions did not seem to be clinically relevant. Hydrocotarnine also did not cause a significant change in the ATPase activity of human P-gp membranes, suggesting that it is not an inhibitor of P-gp. Furthermore, mice were intraperitoneally injected with hydrocotarnine for 14 days and the mRNA levels of major CYP isozymes and P-gp in the liver and small intestine were determined by real-time RT-PCR. As a result, none of the mRNAs investigated showed a significant change in their levels by hydrocotarnine treatment. In conclusion, it is unlikely that the potentiation of oxycodone effect by hydrocotarnine involves its effect on CYP and P-gp. The findings also demonstrate that hydrocotarnine is unlikely to cause drug interactions via CYP or P-gp.
Ito
Kiyomi
K
Department of Clinical Pharmacokinetics, Hoshi University, Tokyo, Japan.
Kubota
Yu
Y
Toda
Takahiro
T
Suto
Satoshi
S
Ikarashi
Nobutomo
N
Sugiyama
Kiyoshi
K
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis* / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000378:metabolism; D004347:Drug Interactions; D006801:Humans; D007421:Intestine, Small / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010098:Oxycodone / Q000493:pharmacokinetics; D011994:Recombinant Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013379:Substrate Specificity; D044005:Tetrahydroisoquinolines / Q000493:pharmacokinetics* / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D065607:Cytochrome P-450 Enzyme Inhibitors; D011994:Recombinant Proteins; D044005:Tetrahydroisoquinolines; D003577:Cytochrome P-450 Enzyme System; D010098:Oxycodone; D000251:Adenosine Triphosphatases; C024594:hydrocotarnine