CYP3A4 inhibitor mechanisms

Some of the clinically important drugs that have been identified to be mechanism-based CYP3A4 inhibitors include antibiotics (e g., erythromycin), anticancer drugs (e.g., irinotecan), antidepressants (e g., fluoxetine and paroxetine), anti-FIIV agents (e.g., ritonavir and... 

Quasi-irreversible inhibition is observed when CYP metabohsm produces an intermediate that can form a stable metabolite-intermediate MI) complex. This is another example of mechanism-based inhibition. Erythromycin is one such quasi-irreversible CYP3A4 inhibitor. Upon didemethylation of its tertiary amine group and subsequent oxidation, the resulting nitroso species forms a tight complex with the Fe(II) atom of the CYP s heme unit. Unhke truly irreversible adducts, such complexes can be broken up, say by oxidation with potassium ferricyanide, but under normal physiological conditions this obviously doesn t happen. 

Indinavir is a protease inhibitor used in the management of HIV infection. CYP3A4 mediates the biotransformation of indinavir in vitro (85,86), and in vivo, indinavir has been shown to be a potent competitive and mechanism-based inhibitor of CYP3A4 (85,87). Piscitelli and coworkers (80) examined the effect of St. John s wort (300 mg t.i.d. x 14 days) administration on indinavir (800 mg q.i.d. x 8 hr x four doses) exposure in eight healthy volunteers (two females). The administration of St. John s wort for 14 days resulted in a significant 54 /o reduction in the indinavir eight-hour area under the concentration-time curve, from 35.8 13.0 to 15.6 5.8 pg X hr/mL. The authors conclude that the magnitude in the reduction in indinavir concentrations may result in the development of antiretroviral resistance and subsequent treatment failure. 

Buspirone Mechanism uncertain Partial agonist at 5-HT receptors but affinity for D2 receptors also possible Slow onset (1-2 weeks) of anxiolytic effects t minimal psychomotor impairment—no additive CNS depression with sedative-hypnotic drugs Generalized anxiety states Oral activity forms active metabolite short half-life Toxicity Tachycardia paresthesias t gastrointestinal distress Interactions CYP3A4 inducers and inhibitors... 

Mechanism-based inhibitors or suicide substrates seem to be particularly prevalent with CYP3A4. Such compounds are substrates for the enzyme, but metabolism is believed to form products that deactivate the enzyme. Several macrolide antibiotics, generally involving a tertiary amine function, are able to inhibit CYP3A4 in this manner (147,148). Erythromycin is one of the most widely used examples of this type of interaction, although there are other commonly prescribed agents that inactivate CYP3A4 (149-151), and a consideration of this phenomenon partially explains a number of interactions that are not readily explained by the conventional in vitro data (152). 

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