Cytochrome P450-mediated hepatic metabolism

Vuppugalla R, Mehvar R (2004) Hepatic Disposition and Effects of Nitric Oxide Donors Rapid and Concentration-Dependent Reduction in the Cytochrome P450-Mediated Drug Metabolism in Isolated Perfused Rat Livers. J Pharmacol Exp Ther (in press)... 

Isosteric substitution of the C-2 hydrogen atom of valproic acid (12) with a fluorine atom affords 2-fluorovalproic acid (22), which causes significantly less hepatoxicity than valproic acid, although a reduction in anticonvulsant properties is also observed [59, 60]. The hepatoxicity of 12 involves hepatic cytochrome P450-mediated metabolism to its 4-ene metabolite (14), which undergoes further metabolism, specifically mitchondrial (3-oxidation, to provide ( )-2-propyl-2,4-pentadienoic add (23), a reactive electrophilic metabolite [59, 60]. 

Oxybutynin has a relatively low oral bioavailability (6%) due to an extensive first-past presystemic metabolism after administration [194], Indeed, the absence of intact oxybutynin in urine suggests that the major elimination pathway of this drug is hepatic metabolism [195]. The compound is readily converted to its stable toxic metabolite, iV-desethyloxybutynin by cytochrome P450-mediated oxidation [196], Following oral administration of oxybutynin, peak plasma concentrations are reached within 1 h. The short half-life of this drug (less than 2 h), when administered as a conventional oral formulation, necessitates multiple 5 mg daily dosing [197],... 

In hepatic microsomes, omeprazole inhibited cytochrome P450-mediated metabolic reactions in vitro. This effect was comparable to the inhibition caused by cimetidine with respect to the extent of the inhibitory effect and the effective concentrations [110]. Under well-defined clinical conditions, an... 

Valproic acid is rapidly distributed and the plasma protein binding is concentration dependent (18). As previously noted, valproic acid is extensively metabolized, primarily in the liver, with about 30-50% of the drug excreted as the glucuronide (phase II metabolism) in the urine, about 30-40%by the phase I mitochondrial j3-oxidation pathway, and about 10-20% by microsomal cytochrome P450-mediated hy droxylation/dehydrogena-tion of the side chain that provides the major phase I metabolites (36). The metabolites of valproic acid have been thought to be the cause of a rare, but fatal hepatotoxicity (35). The synthetic ( )-2,4-diene VPA has been shown to induce the same hepatic microve-sicular steatosis seen in patients, in chronic administration studies in rats (36). The ultimate causative factor (s) of hepatoxicity of valproic acid currently remain undefined (28,29). 

C. J. Decker, M. S. Rashed, T. A. Baillie, D. Maltby, M. A. Correia, Oxidative Metabolism of Spironolactone Evidence for the Involvement of Electrophilic Thiosteroid Species in Drug-Mediated Destruction of Rat Hepatic Cytochrome P450 , Biochemistry 1989, 28, 5128-5136. 

MefaboZ/s/T - Tolterodine undergoes extensive and variable first-pass hepatic metabolism following oral dosing. The primary metabolic route involves the oxidation of the 5-methyl group mediated by the cytochrome P450 2D6 leading to the formation of an active 5-hydroxymethyl metabolite. Further metabolism leads to formation of the 5-carboxylic acid and N-dealkylated 5-carboxylic acid metabolites, which account for approximately 51% and approximately 29% of the metabolites recovered in the urine, respectively. 

Buprenorphine is metabolized by the liver mediated by cytochrome P450 3A4, and its clearance is related to hepatic blood flow. Plasma protein binding is about 96%. The mean elimination half-life from plasma is 37 hours. 

Species differences in the metabolism of di(2-ethylhexyl) phthalate have been reported and attempts have been made to explain the susceptibility of animals to di(2-ethylhexyl) phthalate-induced hepatic peroxisome proliferation based on their metabolic profiles (Doull et al., 1999). As mentioned above, the bulk of a di(2-ethylhexyl) phthalate dose is absorbed as the mono-ester, mono(2-ethylhexyl) phthalate, and following absorption this metabolite is subjected to extensive oxidative metabolism mediated by cytochrome P450 enzymes (Albro Lavenhar, 1989 Astill, 1989 Huber et al., 1996 Doull et al., 1999). The metabolism of mono(2-ethylhexyl) phthalate has been summarized by Doull et al. (1999) as follows (see Figure 1) ... 

Pantoprazole undergoes extensive hepatic metabolism in humans via cytochrome P450 (CYP)-mediated oxidation, followed by sulfate conjugation [1]. The major metabolites of pantoprazole are shown in Figure 14. 

Decker C, Rashed M, Baillie T, et al. Oxidative metabolism of spironolactone evidence for the involvement of electrophilic thiosteroid species in chug-mediated destruction of rat hepatic cytochrome P450. Biochem Pharmacol 1989 28 5128-5136. 

Lamba JK, Lin YS, Schuety EG, Thummel KE (2002) Genetic contribution to variable human CYP3A-mediated metabolism. Adv Drug Del Rev 54 1271-1294 Lee JI, Chaves-Gnecco D, Amico JA et al. (2002) Application of simultaneous midazolam administration for hepatic and intestinal cytochrome P450 3A phenotyping. Clin Pharmacol Ther 72 718-728... 

Hepatic metabolism of topotecan, mediated by cytochrome P450 isozymes, is of minor quantitative importance (26-29,58). Metabolic pathways include N-dealkylation (producing A-demethyltopotecan) and glucuronidation. There is some evidence that potent inhibitors or inducers of CYP3A4 alter the clearance of topotecan (58). 

Research on the mechanism of the onset of hypercholesterolemia during a state of marginal vitamin C deficiency (6,21,22) has led to the finding that ascorbate is necessary for cholesterol transformation to bile acids (23) at the rate-limiting reaction of bile-acid biosynthesis. That limiting step is the 7 -hydroxylation of cholesterol (6,24r-26). The action of ascorbate on 7 -hydroxylation is not a direct one because in vitro added L-ascorbic acid has no effect (24,27). The effect is mediated by the intervention of ascorbate in the metabolism of cytochrome P450 in the endoplasmatic reticulum of the hepatal cell (6,24), Through a... 

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