Method for predicting the risk of drug-drug interactions involving inhibition of intestinal CYP3A4 and P-glycoprotein.
To develop a method to predict the risk of drug-drug interactions involving the inhibition of intestinal CYP3A4 or P-glycoprotein, data from clinical drug-drug interaction studies of CYP3A4 and/or P-glycoprotein substrates were analysed. The ratio of inhibitor dose (Dose(i)) to inhibition constant (K(i)), termed the drug-interaction number, was used to index intestinal drug-drug interaction. From the analysis, it was found that (1) CYP3A4 inhibitors with a drug-interaction number below 2.8 L have a low risk of interacting with substrates which exhibit intestinal first-pass metabolism and those with a drug-interaction number above 9.4 L have a high risk; (2) P-glycoprotein inhibitors with a drug-interaction number below 10.8 L have a low risk of interacting with P-glycoprotein substrates and those with a drug-interaction number above 27.9 L have a high risk; and (3) the drug-interaction number indexes, 2.8 L and 9.4 L for CYP3A4 and 10.8 L and 27.9 L for P-glycoprotein were validated by data from dual CYP3A4/P-glycoprotein substrates. In conclusion, the drug-interaction number is useful for classifying the risk of drug-drug interactions involving the inhibition of intestinal CYP3A4 and P-glycoprotein. This drug-interaction number-based approach is similar to the method that the US Food and Drug Administration (USFDA) recently proposed in the draft guidance for predicting P-glycoprotein-mediated drug-drug interaction.
Tachibana
T
T
Pre-Clinical Research Department, Research Division, Chugai Pharmaceutical Co., Ltd, Shizuoka, Japan. tachibanatth@chugai-pharm.co.jp
Kato
M
M
Watanabe
T
T
Mitsui
T
T
Sugiyama
Y
Y
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D019540:Area Under Curve; D001682:Biological Availability; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004347:Drug Interactions; D006801:Humans; D007408:Intestinal Absorption; D007422:Intestines / Q000201:enzymology*; D010600:Pharmacology / Q000379:methods*; D012307:Risk Factors; D012995:Solubility; D013379:Substrate Specificity
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D065692:Cytochrome P-450 CYP3A Inhibitors; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human