Which concentration of the inhibitor should be used to predict in vivo drug interactions from in vitro data?
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.
Ito
Kiyomi
K
School of Pharmaceutical Sciences, Kitasato University, Tokyo 108-8641, Japan.
Chiba
Koji
K
Horikawa
Masato
M
Ishigami
Michi
M
Mizuno
Naomi
N
Aoki
Jun
J
Gotoh
Yasumasa
Y
Iwatsubo
Takafumi
T
Kanamitsu
Shin-ichi
S
Kato
Motohiro
M
Kawahara
Iichiro
I
Niinuma
Kayoko
K
Nishino
Akiko
A
Sato
Norihito
N
Tsukamoto
Yuko
Y
Ueda
Kaoru
K
Itoh
Tomoo
T
Sugiyama
Yuichi
Y
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
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors