Cytochrome P450 3A4 in vivo ketoconazole competitive inhibition: determination of Ki and dangers associated with high clearance drugs in general.

Assuming complete hepatic substrate metabolism and system linearity, quantitative effects of in vivo competitive inhibition are investigated. Following oral administration of a substrate in the presence of a competitive inhibitor, determination of the inhibition constant (Ki) is possible when plasma concentration-time profiles of both substrate and inhibitor are available. When triazolam is the P450 3A4 substrate and ketoconazole the competitive inhibitor, Ki approximately 1.2 microg/mL in humans. The effects of competitive inhibition can be divided into two components: first-pass hepatic metabolism and systemic metabolism. For drugs with high hepatic extraction ratios, the impact of competitive inhibition on hepatic first-pass metabolism can be particularly dramatic. For example, human terfenadine hepatic extraction goes from 95% in the absence of a competitive inhibitor to 35% in the presence of one (ketoconazole, 200 mg po Q 12 h dosed to steady-state). First-pass extraction therefore goes from 5% in the absence of the inhibitor to 65% in its presence. The combined effect on first-pass and systemic metabolism produces an approximate 37 fold increase in terfenadine area under the plasma concentration-time curve. Assuming intact drug is active and/or toxic, development of metabolized drugs with extensive first-pass metabolism should be avoided if possible, since inhibition of metabolism may lead to profound increases in exposure.