INHIBITION OF DRUG METABOLISM

 One drug can competitively inhibit the metabolism of another if it utilizes the same enzyme or cofactors. However, such interactions are not as common as one would expect, because often different drugs are substrates for different CY P-450 isoenzymes. It is thus important to know the CYP isoenzyme(s) that carry out the metabolism of a particular drug. A drug may inhibit one isoenzyme while being itself a substrate of another isoenzyme, e.g. quinidine is metabolized mainly by CYP3A4 but inhibits CYP2D6. Also most drugs, at therapeutic concentrations, are metabolized by non-saturation kinetics, i.e. the enzyme is present in excess. Clinically significant inhibition of drug metabolism occurs in case of drugs having affinity for the same isoenzyme, specially if they are metabolized by saturation kinetics or if kinetics changes from first orde

  Drugs that inhibit drug metabolizing enzymes

  Allopurinol                             Amiodarone

 Omeprazole                             Propoxyphene

 Erythromycin                          Isoniazid

 Clarithromycin                       Cimetidine

 Chloramphenicol                   Quinidine

 Ketoconazole                         Disulfiram

 Itraconazole                           Diltiazem

 Metronidazole                       Verapamil

 Ciprofloxacin                        MAO inhibitors

 Sulfonamides                        Ritonavir

 (and other Fluoxetine           (and HIV protease  inhibitors)

 other SSRIs)

to zero order over the therapeutic range (capacity limited metabolism). Obviously, inhibition of drug metabolism occurs in a dose related manner and can precipitate toxicity of the object drug (whose metabolism has been inhibited). Because enzyme inhibition occurs by direct effect on the enzyme, it has a fast time course (within hours) compared to enzyme induction (see below). Metabolism of drugs with high hepatic extraction is dependent on liver blood flow (blood flow limited metabolism). Propranolol reduces rate of lidocaine metabolism by decreasing hepatic blood flow. Some other drugs whose rate of metabolism is limited by hepatic blood flow are morphine, propranolol, verapamil and imipramine.