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 /K i ratio, where [I] u is the unbound concentration around the enzyme and K i 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 /K i 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 /K i ratios, the pharmacokinetic parameters of each drug were obtained from the literature, together with their reported K i values determined in in vitro studies using human liver microsomes.For most of the drugs with a calculated [I] in,max,u /K i 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 /K i and [I] max /K i 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]

The impact of breast cancer resistant protein (BCRP/ABCG2) on drug transport across Caco-2 cell monolayers

For developing oral drugs, it is necessary to predict the oral absorption of new chemical entities accurately. However, it is difficult because of the involvement of efflux transporters, including P-glycoprotein (P-gp), in their absorption process. In this study, we conducted a comparative analysis on the inhibitory activities of seven P-gp inhibitors (cyclosporin A, GF120918, LY335979, XR9576, WK-X-34, VX-710, and OC144-093) to evaluate the effect of P-gp on drug absorption. GF120918, LY335979, and XR9576 significantly decreased the basal-to-apical transport of paclitaxel, a P-gp substrate, across Caco-2 cell monolayers. GF120918 also inhibited the basal-to-apical transport of mitoxantrone, a breast cancer resistance protein (BCRP) substrate, in Caco-2 cells, whereas LY335979 hardly affected the mitoxantrone transport. In addition, the absorption rate of paclitaxel after oral administration in wild-type mice was significantly increased by pretreatment with LY335979, and it was similar to that in mdr1a/1b knockout mice. Moreover, the absorption rate of topotecan, a BCRP substrate, in wild-type mice pretreated with LY335979 was similar to that in mdr1a/1b knockout mice but significantly lower than that in bcrp knockout mice. These results indicate that LY335979 has a selective inhibitory activity for P-gp, and would be useful for evaluating the contribution of P-gp to drug absorption.