Clinical outcomes and management of mechanism-based inhibition of cytochrome P450 3A4

Abstract

Abstract:Mechanism-based inhibition of cytochrome P450 (CYP) 3A4 is characterized by NADPH-, time-, and concentration-dependent enzyme inactivation, occurring when some drugs are converted by CYPs to reactive metabolites. Such inhibition of CYP3A4 can be due to the chemical modification of the heme, the protein, or both as a result of covalent binding of modified heme to the protein. The inactivation of CYP3A4 by drugs has important clinical significance as it metabolizes approximately 60% of therapeutic drugs, and its inhibition frequently causes unfavorable drug-drug interactions and toxicity. The clinical outcomes due to CYP3A4 inactivation depend on many factors associated with the enzyme, drugs, and patients. Clinical professionals should adopt proper approaches when using drugs that are mechanism-based CYP3A4 inhibitors. These include early identification of drugs behaving as CYP3A4 inactivators, rational use of such drugs (eg, safe drug combination regimen, dose adjustment, or discontinuation of therapy when toxic drug interactions occur), therapeutic drug monitoring, and predicting the risks for potential drug-drug interactions. A good understanding of CYP3A4 inactivation and proper clinical management are needed by clinical professionals when these drugs are used.

Mechanism-Based Inactivation of Cytochrome P450 3A4 by Mibefradil through Heme Destruction

“…Mibefradil was voluntarily withdrawn from the market in 1998 because of the potential for rhabdomyolysis, renal failure, or bradycardia when it was coadministered with other drugs (Paoletti et al, 2002). The measured plasma concentrations of drugs such as simvastatin, tacrolimus, cyclosporine, and digoxin exhibited a marked increase when coadministered with mibefradil, because of inhibition of either CYP3A or the cellular efflux transporter P-glycoprotein by mibefradil (Zhou et al, 2005). After withdrawal from the market, mibefradil was shown to be a potent mechanism-based inactivator of CYP3A4 (Prueksaritanont et al, 1999).…”

Use of a Multistaged Time-Dependent Inhibition Assay to Assess the Impact of Intestinal Metabolism on Drug-Drug Interaction Potential

“…These studies suggested that inactivation by raloxifene occurs through alkylation of Cys239 by the diquinone methide intermediate. However, no significant drug-drug interactions due to inhibition of metabolism of CYP3A4 substrates have been reported, nor does the package insert provide an associated warning even though the K I and k inact values of raloxifene determined in the in vitro mechanism-based inhibition studies are similar to known mechanism-based inactivators of CYP3A4 that cause severe drug-drug interactions, therefore emphasizing the importance of dose and exposure (Zhou et al, 2005). The disparity between potent inactivation of CYP3A4 and the lack of drug-drug interactions could also be attributed to a decrease in raloxifene exposure due to presystemic glucuronidation.…”

The risk of hypotension following co-prescription of macrolide antibiotics and calcium-channel blockers

“…2,3 In the presence of an inhibitor of this isoenzyme, drugs that require cytochrome P450 3A4 for their metabolism will accumulate, potentially leading to toxicity. 4,5 Cytochrome P450 3A4 has many substrates of clinical relevance, but the calcium-channel blockers are of particular importance. These drugs are widely used for several chronic conditions, including hypertension and coronary artery disease.…”