Cytochrome drug clearance

Erythromycin inhibits a cytochrome P450 isoenzyme and impairs the metabolism of theophylline, warfarin, carbamazepine and methylprednisolone. The mean reduction in drug clearance is 20-25%. 

Cholestasis is a condition characterized by impaired flow of bile, due to physical obstruction of the biliary tree or decreased bile secretion by the liver. Cholestasis produces alterations of enzyme activity in the liver (cytochrome P450) as well as altered transporter expression, with associated effects on drug clearance. As discussed previously, cholestasis can occur through inhibition of the canalicular membrane transporter, BSEP. In response to cholestasis, however, the liver has adaptive mechanisms to minimize cellular accumulation of toxic bile salts. These include upregulation of MRP3 to increase sinusoidal efflux, and downregulation of Na -taurocholate cotransporting polypeptide (NTCP), which mediates bile salt uptake from the blood to the liver. 

Kilford PJ, Stringer R, Sohal B, Houston JB, Galetin A. Prediction of drug clearance by glucuronidation from in vitro data Use of combined cytochrome P450 and UDP-glucuronosyltransferase cofactors in alamethicin-activated human liver microsomes. Drug Metab Dispos 2009 37(1) 82—89. 

Use of zileuton is uncommon due to the need for dosing four times a day, potential drug interactions, and the potential for hepatotoxicity with the resulting need for frequent monitoring of liver enzymes. In patients started on zileuton, serum alanine aminotransferase concentrations should be monitored before treatment begins, monthly for the first 3 months, every 2 to 3 months for the remainder of the first year, and then periodically thereafter for as long as the patient continues to receive the medication. Zileuton also inhibits the cytochrome P-450 (CYP) mixed function enzyme system and has been shown to decrease the clearance of theophylline, R-warfarin and propranolol.34... 

Tobacco smoke contains chemicals that induce the cytochrome P-450 isoenzymes 1A1,1A2, and 2E1. Theophylline is metabolized by 1A2 and 2E1, and therefore smoking leads to increased clearance and subsequently decreased plasma levels of the drug.15 Because most patients with COPD are current or past smokers, it is important to assess current tobacco use and adjust the theophylline dose as required based on altered plasma theophylline levels if tobacco use changes. 

CKD may alter nonrenal clearance of drugs as the result of changes in cytochrome P450-mediated metabolism in the hver and other organs. The clinical reductions in nonrenal clearance in CKD are generally proportional to the reductions in glomerular filtration rate (Table 77-1). 

Compound A appears mainly as unchanged drug in the bile whereas compound B appears partly as metabolites. Administration of ketoconazole, a potent cytochrome P450 inhibitor, to the preparation dramatically decreases the metabolism of B and the compound appears mainly as unchanged material in the bile. Despite the inhibition of metabolism, hepatic extraction remains high (0.9). This indicates that clearance is dependent on hepatic uptake, via a transporter system, for removal of the compounds from the circulation. Metabolism of compound B is a process that occurs subsequent to this rate-determining step and does not influence overall clearance. This model for the various processes involved in the clearance of these compounds is illustrated in Figure 5.4. 

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