2. CYP Inhibition

Human hepatic microsomes are most frequently used as an experimental model to evaluate the inhibitory mechanism of drug-drug interactions. The most effective application is to use isozyme-specific inhibitors to determine which CYP iso-zymes are responsible for drug metabolism. The principle is that drugs metabolized by the same isozymes would have inhibitory effects on the metabolism of each other. Primary hepatocytes represent an experimental system that can substantiate findings with microsomes. For a drug to inhibit the metabolism of another drug, it needs to be present in the hepatocytes in vivo. The intracellular concentration is dependent on both membrane permeability and the activity of the multiple drug resistance protein that actively pumps xenobiotics out of the hepatocytes. It is therefore necessary to confirm findings in microsomes with an intact cell system such as hepatocytes and liver slices.

Terfenadine has been associated with several adverse drug interactions. The metabolism of terfenadine was studied using primary human and rat hepatocytes and compared with results from an immortalized cell line, HepG2 [11,19]. While all the three-cell systems extensively metabolize terfenadine, human hepatocytes were found to produce both C-oxidation and N-dealkylation products. Rat hepatocytes and HepG2 cells produce only C-oxidation products. Further, the known inhibitors of CYP3A, the isozyme believed to be mainly responsible for terfenadine metabolism: ketoconazole, erythromycin, and troleandomycin, inhibited ter-fenadine metabolism in human but not in rat hepatocytes. These results suggest that primary human hepatocytes represent a more appropriate experimental model than rat hepatocytes or HepG2 cells for the evaluation of drug-drug interactions [11,18,19]. Intact human hepatocytes are now routinely used for the evaluation of the potential of xenobiotics to inhibit CYP isoforms. Results with known CYP inhibitors provide the expected responses. The potent and specific CYP inhibitors for intact human hepatocytes are furafylline for CYP1A2, quinidine for CYP2D6, and ketoconazole for CYP3A4 [18].

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