Inhibition of cytochrome P450 (CYP450) isoforms by isoniazid: Potent inhibition of CYP2C19 and CYP3A

Isoniazid (INN) remains the most safe and cost-effective drug for the treat ment and prophylaxis of tuberculosis. The use of INH has increased over the past years, largely as a result of the coepidemic of human immunodeficienc y virus infection. It is frequently given chronically to critically ill pat ients who are coprescribed multiple medications. The ability of INH to elev ate the concentrations in plasma and/or toxicity of coadministered drugs, i ncluding those of narrow therapeutic range (e.g., phenytoin), has been docu mented in humans, but the mechanisms involved are not well understood. Usin g human liver microsomes (HLMs), we tested the inhibitory effect of INH on the activity of common drug-metabolizing human cytochrome P450 (CYP450) iso forms using isoform-specific substrate probe reactions. Incubation experime nts were performed at a single concentration of each substrate probe at its K-m value with a range of INH concentrations. CYP2C19 and CYP3A were inhib ited potently by INH in a concentration-dependent manner. At 50 muM INH (si milar to6.86 mug/ml), the activities of these isoforms decreased by similar to 40%. INH did not show significant inhibition (<10% at 50 <mu>M) of othe r isoforms (CYP2C9, CYP1A2, and CYP2D6). To accurately estimate the inhibit ion constants (K-i values) for each isoform, four concentrations of INH wer e incubated across a range of five concentrations of specific substrate pro bes. The mean K-i values (+/- standard deviation) for the inhibition of CYP 2C19 by INH in HLMs and recombinant human CYP2C19 were 25.4 +/- 6.2 and 13 +/- 2.4 muM, respectively. INH showed potent noncompetitive inhibition of C YP3A (K-i = 51.8 +/- 2.5 to 75.9 +/- 7.8 muM, depending on the substrate us ed). INH was a weak noncompetitive inhibitor of CYP2E1 (K-i = 110 +/- 33 mu M) and a competitive inhibitor of CYP2D6 (K-i = 126 +/- 23 muM), but the me an K-i values for the inhibition of CYP2C9 and CYP1A2 were above 500 muM. I nhibition of one or both CYP2C19 and CYP3A isoforms is the likely mechanism by which INH slows the elimination of coadministered drugs, including phen ytoin, carbamazepine, diazepam, triazolam, and primidone. Slow acetylators of INH may be at greater risk for adverse drug interactions, as the degree of inhibition was concentration dependent. These data provide a rational ba sis for understanding drug interaction with INH and predict that other drug s metabolized by these two enzymes may also interact.