Pharmacokinetic Interactions that Increase Drug Delivery to the Site of Action

INHIBITION OF DRUG-METABOLIZING ENZYMES For drugs whose clearance depends on biotransformation, inhibition of a metabolizing enzyme leads to reduced clearance, prolonged t1/2, and drug accumulation during maintenance therapy, sometimes with severe adverse effects. Knowledge of the CYP isoforms that catalyze the principal pathways of drug metabolism provides a basis for understanding and even predicting drug interactions (see Chapter 3).

Hepatic CYP3A isozymes catalyze the metabolism of many drugs that are subject to significant drug interactions owing to inhibition of metabolism. Drugs metabolized predominantly by CYP3A isozymes include immunosuppressants (e.g., cyclosporine and tacrolimus); HMG-CoA reductase inhibitors (e.g., lovastatin, simvastatin, and atorvastatin); HIV protease inhibitors (e.g., indinavir, nelfinavir, saquinavir, amprinavir, and ritonavir); Ca2+ channel antagonists (e.g., felodipine, nifedipine, nisoldipine, and diltiazem); glucocorticoids (e.g., dexamethasone and methylpred-nisolone); benzodiazepines (e.g., alprazolam, midazolam, and triazolam); and lidocaine.

The inhibition of CYP3A isoforms may vary even among structurally related members of a given drug class. For example, the antifungal azoles ketoconazole and itraconazole potently inhibit CYP3A enzymes, whereas the related fluconazole inhibits minimally except at high doses or in the setting of renal insufficiency. Similarly, certain macrolide antibiotics (e.g., erythromycin and clar-ithromycin) potently inhibit CYP3A isoforms, but azithromycin does not. In one instance, the inhibition of CYP3A4 activity is turned to therapeutic advantage: the HIV protease inhibitor ritonavir inhibits CYP3A4 activity; when coadministered with other protease inhibitors metabolized by this pathway, ritonavir increases their half-lives and permits less frequent dosing.

Drug interactions mediated by CYP3A inhibition can be severe (e.g., nephrotoxicity induced by cyclosporine and tacrolimus and rhabdomyolysis resulting from increased levels of statins). Whenever an inhibitor of the CYP3A isoforms is administered, the clinician must be cognizant of the potential for serious interactions with drugs metabolized by CYP3A.

Drug interactions also can result from inhibition of other CYPs. Amiodarone and its active metabolite desethylamiodarone promiscuously inhibit several CYPs, including CYP2C9, the principal enzyme that eliminates the active S-enantiomer of warfarin. Because many patients treated with amiodarone (e.g., subjects with atrial fibrillation) are also receiving warfarin, the potential exists for major bleeding complications.

Knowledge of the specific pathways of metabolism of a drug and the molecular mechanisms of enzyme induction can help to identify potential interactions; thus, the pathways of drug metabolism often are determined during preclinical drug development. For example, if in vitro studies indicate that a compound is metabolized by CYP3A4, studies can focus on commonly used drugs that either inhibit (e.g., ketoconazole) or induce (e.g., rifampin) this enzyme. Other probes for the evaluation of potential drug interactions targeted at human CYPs include midazolam or erythromycin for CYP3A4 and dextromethorphan for CYP2D6.

INHIBITION OF DRUG TRANSPORT Drug transporters are key determinants of the availability of certain drugs to their site(s) of action, and clinically significant drug interactions can result from inhibition of drug transporters (see Chapter 2). P-glycoprotein, which actively transports multiple chemotherapeutic drugs out of cancer cells and renders them resistant to drug action, is expressed on the luminal aspect of intestinal epithelial cells (where it functions to inhibit xeno-biotic absorption), on the luminal surface of renal tubular cells, and on the canalicular aspect of hepatocytes. Since this transporter is responsible for the elimination of certain drugs (e.g., digoxin), inhibition of P-glycoprotein-mediated transport results in increased plasma levels of drug at steady state. Inhibitors of P-glycoprotein include verapamil, diltiazem, amiodarone, quinidine, ketocona-zole, itraconazole, and erythromycin. P-glycoprotein on the capillary endothelium that forms the blood-brain barrier exports drugs from the brain, and inhibition of P-glycoprotein enhances CNS distribution of some drugs (e.g., HIV protease inhibitors).

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