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1.  Which concentration of the inhibitor should be used to predict in vivo drug interactions from in vitro data? 
AAPS PharmSci  2002;4(4):53-60.
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.
doi:10.1208/ps040425
PMCID: PMC2751314  PMID: 12645997
Drug interaction; metabolism; quantitative prediction
2.  Comparative studies to determine the selective inhibitors for P-glycoprotein and cytochrome P 4503A4 
AAPS PharmSci  1999;1(4):14-19.
It has been suggested that cytochrome P450 3A4 (CYP3A4) and MDR1 P-glycoprotein (P-gp) act synergistically to limit the bioavailability of orally administered agents. In order to determine the relative role of these proteins, it is essential to identify a selective inhibitor for either P-gp or CYP3A4. In the present investigation, comparative studies were performed to examine the effect of inhibitors on the function of these proteins. The IC50 of P-gp function, determined by examining the inhibition of the transcellular transport of vinblastine across Caco-2 monolayers, was in the order PSC833 ≪ ketoconazole, verapamil ≪ N-(2(R)-hydroxy-1(S)-indanyl)-5-(2(S)-(1,1-dimethylethylaminocarbonyl)-4-(furo(2,3-b)pyridin-5-yl) methyl)piperazin-1-yl)-4(S)-hydroxy-2(R)-phenylmethylpentanamide (L-754,394). In contrast, the IC50 of CYP3A4 function, determined by examining the inhibition of the metabolism of midazolam by intestinal and liver microsomes, was in the order L-754,384 ≪ketoconazole≪ PSC 833 and verapamil. The ratio of IC50 for P-gp to that for CYP3A4 was more than 200 for L-754,394,60 ∼ 150 for ketoconazole, 1.5 for verapamil, and 0.05 for PSC 833. Collectively, it was demonstrated that PSC 833 and L-754,394 can be used as selective inhibitors of P-gp and CYP3A4, respectively.
doi:10.1208/ps010418
PMCID: PMC2751348  PMID: 11741214

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