Pharmacokinetic-Pharmacodynamic Consequences and Clinical Relevance of Cytochrome P450 3A4 Inhibition

Abstract

Drug interactions occur when the efficacy or toxicity of a medication is changed by administration of another substance. Pharmacokinetic interactions often occur as a result of a change in drug metabolism. Cytochrome P450 (CYP) 3A4 oxidises a broad spectrum of drugs by a number of metabolic processes. The location of CYP3A4 in the small bowel and liver permits an effect on both presystemic and systemic drug disposition. Some interactions with CYP3A4 inhibitors may also involve inhibition of P-glycoprotein. Clinically important CYP3A4 inhibitors include itraconazole, ketoconazole, clarithromycin, erythromycin, nefazodone, ritonavir and grapefruit juice. Torsades de pointes, a life-threatening ventricular arrhythmia associated with QT prolongation, can occur when these inhibitors are coadministered with terfenadine, astemizole, cisapride or pimozide. Rhabdomyolysis has been associated with the coadministration of some 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors ('statins') and CYP3A4 inhibitors. Symptomatic hypotension may occur when CYP3A4 inhibitors are given with some dihydropyridine calcium antagonists, as well with the phosphodiesterase inhibitor sildenafil. Excessive sedation can result from concomitant administration of benzodiazepine (midazolam, triazolam, alprazolam or diazepam) or nonbenzodiazepine (zopiclone and buspirone) hypnosedatives with CYP3A4 inhibitors. Ataxia can occur with carbamazepine, and ergotism with ergotamine, following the addition of a CYP3A4 inhibitor. Beneficial drug interactions can occur. Administration of a CYP3A4 inhibitor with cyclosporin may allow reduction of the dosage and cost of the immunosuppressant. Certain HIV protease inhibitors, e.g. saquinavir, have low oral bioavailability that can be profoundly increased by the addition of ritonavir. The clinical importance of any drug interaction depends on factors that are drug-, patient- and administration-related. Generally, a doubling or more in plasma drug concentration has the potential for enhanced adverse or beneficial drug response. Less pronounced pharmacokinetic interactions may still be clinically important for drugs with a steep concentration-response relationship or narrow therapeutic index. In most cases, the extent of drug interaction varies markedly among individuals; this is likely to be dependent on interindividual differences in CYP3A4 tissue content, pre-existing medical conditions and, possibly, age. Interactions may occur under single dose conditions or only at steady state. The pharmacodynamic consequences may or may not closely follow pharmacokinetic changes. Drug interactions may be most apparent when patients are stabilised on the affected drug and the CYP3A4 inhibitor is then added to the regimen. Temporal relationships between the administration of the drug and CYP3A4 inhibitor may be important in determining the extent of the interaction.

Dapoxetine, a novel treatment for premature ejaculation, does not have pharmacokinetic interactions with phosphodiesterase-5 inhibitors

“…This is an important finding, as CYP3A4 is involved in the metabolism of many drugs, and inhibition or induction of this enzyme can result in clinically important drug interactions. 22,23 The results of this definitive clinical study, which demonstrated no significant pharmacokinetic interactions of dapoxetine with either sildenafil or tadalafil, are in agreement with what is known about the metabolic pathways for dapoxetine and in vitro CYP inhibition and induction profiles for sildenafil and tadalafil. Dapoxetine is extensively metabolized to numerous phase I and phase II metabolites by multiple enzymes, including CYP3A4 and CYP2D6, and in vitro inhibition and induction studies have shown that dapoxetine is a very weak inhibitor of CYP3A4 (unpublished data).…”

Differential effects of ketoconazole on exposure to temsirolimus following intravenous infusion of temsirolimus

“…Because CYP3A4 is the most abundant CYP isozyme in humans and the pathway responsible for metabolism of numerous xenobiotics (Shimada et al, 1994;Li et al, 1995;Dresser et al, 2000), the potential for drug interaction exists. Using in vitro liver microsome systems, ketoconazole, a potent inhibitor of CYP3A4, decreased the formation of temsirolimus metabolites to 10 -20% of control levels (IC 50 o2 mM) (Cai et al, 2007).…”

Pharmacokinetics and Drug Interactions of Herbal Medicines: A Missing Critical Step in the Phytomedicine/Drug Development Process

“…This assumption is supported by several studies which show that some herbal medicinal products have the capacity to influence plasma levels of drugs (10,11), giving rise to clinical problems of unexpected toxicities and under-treatment seen in different groups of patients. Factors relating to co-administered drugs (dose, dosing regimen, administration route, pharmacokinetic and therapeutic range), herbs (species, dose, dosing regimen, and administration route) and patients (genetic polymorphism, age, gender and pathological conditions) largely determine the extent and thus the clinical relevance of drug interactions with herbs (12). In general terms, the appearance of enhanced drug effects and/or adverse effects is usually associated with a doubling or more in drug plasma concentration (13).…”