Cytochrome P450 inhibitor

Witschi and colleagues19 identified the requirement for metabolic activation of BHT in determining that radioactivity from 14C-labeled BHT became covalently bound to proteins in mouse lung. Both toxicity and protein binding were prevented when mice were treated with cytochrome P450 inhibitors, thereby indicating the... 

DJ Edwards, FH Bellevue, PM Woster. Identification of 6, 7 -dihydroxybergamottin, a cytochrome P450 inhibitor, in grapefruit juice. Drug Metab Dispos 24 1287-1290, 1996. 

The mechanism of toxification of isoniazid was investigated in rats pretreated with inducers or inhibitors of microsomal enzymes or an inhibitor of acylamidases. In animals pretreated with the acylamidase inhibitor bis(4-nitrophenyl) phosphate, isoniazid and acetylisoniazid produced less liver necrosis than in control animals. The treatment had no effect on the necrosis due to acetylhydrazine [173], In animals pretreated with inducers of microsomal cytochrome P450 such as phenobarbital, acetylisoniazid, and acetylhydrazine caused markedly increased necrosis, while pretreatment with cytochrome P450 inhibitors decreased necrosis. In contrast, the toxicity of isoniazid and hydrazine was not modified by phenobarbital pretreatment. From these observations, Trimbell et al. [173] concluded that the hydrolysis of acetylisoniazid is a prerequisite for hepatotoxicity, and that microsomal enzymes transform acetylhydrazine, the product of hydrolysis, to a toxic species. 

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. 

Use caution when coadministering high and prolonged doses of fluticasone with ketoconazole and other known cytochrome P450 inhibitors. 

Cavalli, A. and Recanatini, M. (2002) Looking for selectivity among cytochrome P450s inhibitors. J. Med. Chem. 45, 251-254. 

A wide range of drugs can interact with the barbiturates. Additive effects are seen with other sedatives. The metabolism of other drugs can be induced or the metabolism of the barbiturate can be diminished by cytochrome P450 inhibitors. 

Itraconazole has a broader spectrum than ketoconazole and also the incidence of averse reactions is less. Like the other azoles it is a cytochrome P450 inhibitor. 

Vignette 5.2 Blood Concentrations of Active Metabolites of Substrate Pro-drugs Are Reduced by Cytochrome P450 Inhibitors... 

Erythromycin Prevents bacterial protein synthesis by binding to the 50S ribosomal subunit Bacteriostatic activity against susceptible bacteria Community-acquired pneumonia t pertussis corynebacterial, and chlamydial infections Oral, IV hepatic clearance (half-life 1.5 h) dosed every 6 h cytochrome P450 inhibitor Toxicity Gastrointestinal upset, hepatotoxicity, QTC prolongation... 

Inhalation exposure of male B6C3Fi mice to dichloromethane (6 h, once) led to vacuolation of bronchiolar cells at exposure levels > 2000 ppm [6940 mg/m ], while no effect was obsened at levels < 1000 ppm [3470 mg/m (Foster et al., 1994). Pretreatment with the cytochrome P450 inhibitor piperonyl butoxide (300 mg/kg intraperi-toneally) 1 h before the exposure practically abolished the toxic effect upon bronchiolar cells, while buthionine sulfoximine (1 g/kg intraperitoneally), which decreased the pulmonary glutathione content by 50%, had no such protective effect. In Clara cells isolated after exposure to dichloromethane exposure (> 1000 ppm), the proportion of cells in tlie S-phase was increased. 

Newton, D. J., R. W. Wang, and A. Y. H. Lu. Cytochrome P450 inhibitors Evaluation of specificities in the in vitro metabolism of therapeutic agents by human liver microsomes. Drug Metab. Disp. 23 154-158, 1995. 

Edwards, D.J. Bellevue, F.H. Woster, P.M. Identification of 6 7 dihydroxybergamotin, a cytochrome P450 inhibitor in grapefruit juice. Drug Metab. Dispos. 1996, 24 (12),... 

C, 02]acetate exhibited that " 0-isotope-induced shifts were observed at C-16 and C-18 but not at C-1, C-2 and C-8 [43]. When P. betae was treated with cytochrome P450 inhibitor, ancymidol (1 mM), a less oxidized precursor named probetaenone I (57) was obtained [43]. Tbe structure and stereochemistry were confirmed by extensive NMR analysis and chiral synthesis via the similar route to that of betaenone C (50) [44]. Feeding experiments of C-labeled probetaenone I (57) demonstrated that the intermediate (57) was converted to betaenone B (49) [45]. Isolation of probetaenone I (57)... 

---