title: Which concentration of the inhibitor should be used to predict in vivo drug interactions from in vitro data?
abstract: When the metabolism of a drug is competitively or noncompetitively inhibited by another drug, the degree of in vivo interaction can be evaluated from the [I]u/Ki ratio, where [I]u is the unbound concentration around the enzyme and Ki is the inhibition constant of the inhibitor. In the present study, we evaluated the metabolic inhibition potential of drugs known to be inhibitors or substrates of cytochrome P450 by estimating their [I]u/Ki ratio using literature data. The maximum concentration of the inhibitor in the circulating blood ([I]max), its maximum unbound concentration in the circulating blood ([I]max,u), and its maximum unbound concentration at the inlet to the liver ([I]in,max,u) were used as [I]u, and the results were compared with each other. In order to calculate the [I]u/Ki ratios, the pharmacokinetic parameters of each drug were obtained from the literature, together with their reported Ki values determined in in vitro studies using human liver microsomes. For most of the drugs with a calculated [I]in,max,u/Ki ratio less than 0.25, which applied to about half of the drugs investigated, no in vivo interactions had been reported or "no interaction" was reported in clinical studies. In contrast, the [I]max,u/Ki and [I]max/Ki ratio was calculated to be less than 0.25 for about 90% and 65% of the drugs, respectively, and more than a 1.25-fold increase was reported in the area under the concentration-time curve of the co-administered drug for about 30% of such drugs. These findings indicate that the possibility of underestimation of in vivo interactions (possibility of false-negative prediction) is greater when [I]max,u or [I]max values are used compared with using [I]in,max,u values.
authors.affiliation: School of Pharmaceutical Sciences, Kitasato University, Tokyo 108-8641, Japan.
authors.forename: Kiyomi
authors.initials: K
authors.lastname: Ito
authors.forename: Koji
authors.initials: K
authors.lastname: Chiba
authors.forename: Masato
authors.initials: M
authors.lastname: Horikawa
authors.forename: Michi
authors.initials: M
authors.lastname: Ishigami
authors.forename: Naomi
authors.initials: N
authors.lastname: Mizuno
authors.forename: Jun
authors.initials: J
authors.lastname: Aoki
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Gotoh
authors.forename: Takafumi
authors.initials: T
authors.lastname: Iwatsubo
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Kanamitsu
authors.forename: Motohiro
authors.initials: M
authors.lastname: Kato
authors.forename: Iichiro
authors.initials: I
authors.lastname: Kawahara
authors.forename: Kayoko
authors.initials: K
authors.lastname: Niinuma
authors.forename: Akiko
authors.initials: A
authors.lastname: Nishino
authors.forename: Norihito
authors.initials: N
authors.lastname: Sato
authors.forename: Yuko
authors.initials: Y
authors.lastname: Tsukamoto
authors.forename: Kaoru
authors.initials: K
authors.lastname: Ueda
authors.forename: Tomoo
authors.initials: T
authors.lastname: Itoh
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sugiyama
mesh_terms: D001667:Binding, Competitive; D065607:Cytochrome P-450 Enzyme Inhibitors; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D013379:Substrate Specificity
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors