Cytochrome half-lives

Plasma levels of 3—5 p.g/mL are obtained two hours after adraiinistration of 200 mg ketoconazole. No accumulation in the bloodstream was noted after a 30-wk treatment with this dose. The half-life is approximately eight hours. When ketoconazole is taken with meals, higher plasma levels are obtained. Distribution studies using radioactive ketoconazole in rats show radioactivity mainly in the Hver and the connective tissue. Radioactivity is also present in the subcutaneous tissue and the sebaceous glands. After one dose of 200 mg in humans, ketoconazole is found in urine, saUva, sebum, and cenimen. Like miconazole, the mode of action is based on inhibition of the cytochrome P-450 dependent biosynthesis of ergosterol. This results in disturbed membrane permeabiUty and membrane-bound enzymes (8,10,23,25). 

For recreational use, ketamine is often snorted or smoked with marijuana or tobacco products, but it may also be injected intramuscularly (Weiner et al. 2000). The typical street dose of ketamine ranges from 30 to 300 mg. These amounts are in contrast to the chnical doses used for anesthesia, which range from 2 to 10 mg/kg. Ketamine has a half-life of less than 2 hours and is metabohzed by the cytochrome P450 en2yme system (Koesters et al. 2002 Reich and SUvay 1989). 

Half-life (t1/2) 18-27 hours (adult) greater than 36 hours (elderly or patients with renal impairment) Cytochrome P-450 (CYP450) isoenzyme t1/2 decreases over time due to autoinduction 25-65 hours (initial) 12-1 7 hours (adult multiple dosing) 8-14 hours (children multiple dosing) 2 hours (parent) 9 hours (metabolite) 5-20 hours (adult) 25 hours increases to 59 hours with concomitant valproic acid therapy... 

The exceptional reactivity of aflatoxin B1 exo-8,9-epoxide raises the question of its potential detoxification by EHs. Despite the short half-life, the epoxide does react with DNA (toxification) and glutathione 5-transferases (detoxification), but a role for EH appeared dubious [207], Rat liver or recombinant rat EH has since been shown to provide a modest enhancement of up to 22% in the hydrolysis rate of aflatoxin B1 exo-S,9-epoxide, and to decrease somewhat the genotoxicity of aflatoxin B1 when the ratio of EH to cytochrome P450 is high (ca. 50-fold). Purified human EH provided no such enhancement in hydrolysis, nor did it have a clear effect on genotoxicity. Thus, little evidence exists to support a role for EH in the detoxification of aflatoxin B1 [208],... 

PK Following an oral dose, plasma peak concentration is achieved in approximately 6 hours. About 40% is eliminated through first pass metabolism. The half-life is from 21 to 54 hours and plasma clearance is from 12 to 47 hours. Daily administration will lead to a steady-state plasma concentration in about a week with concentration twice that of the single dose. Metabolism of Zyprexa is by the cytochrome P-450 oxidation. 

The lability of benzylic positions to cytochrome P450 metabolism has been exploited to decrease the unacceptably low clearance and resultant long half-life of various compounds. For example celecoxib, a selective cyclooxygenase inhibitor, has a half-life of 3.5 h in the rat. Early structural leads, represented by compoimds in... 

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. 

CYP 450 Drugs that induce liver enzymes (eg, phenytoin, carbamazepine, phenobarbital) increase the metabolism and clearance of zonisamide and decrease its half-life. Concurrent medication with drugs that induce or inhibit CYP3A4 would be expected to alter serum concentrations of zonisamide. Zonisamide is not expected to interfere with the metabolism of other drugs that are metabolized by cytochrome P450 isozymes. 

Nevirapine has been shown to be an inducer of hepatic cytochrome P450 metabolic enzymes 3A4 and 2B6. The pharmacokinetics of autoinduction are characterized by an approximately 1.5- to 2-fold increase in the apparent oral clearance of nevirapine as treatment continues from a single dose to 2 to 4 weeks of dosing with 200 to 400 mg/day. Auto-induction also results in a corresponding decrease in the terminal phase half-life of nevirapine in plasma from approximately 45 hours (single dose) to approximately 25 to 30 hours following multiple dosing with 200 to 400 mg/day. 

Metaboiism/Excretion - Delavirdine is extensively converted to several inactive metabolites. Delavirdine is primarily metabolized by cytochrome P450 3A (CYP3A), but in vitro data suggest that delavirdine may also be metabolized by CYP2D6. The apparent plasma half-life of delavirdine increases with dose mean half-life following 400 mg 3 times daily is 5.8 hours (range, 2 to 11 hours). 

The plasma protein binding of tacrolimus is approximately 99%. Tacrolimus is bound mainly to albumin and alpha-1-acid glycoprotein and has a high level of association with erythrocytes. It is extensively metabolized by the mixed-function oxidase system, primarily the cytochrome P450 system (CYP3A). The disposition of tacrolimus from whole blood was biphasic with a terminal elimination half-life of 11.7 hours in liver transplant patients. 

The first generation CIO acetal derivatives artemether (Ic) and arteether (Id) both have a short half-life as a consequence of cytochrome P450 catalysed transformation to DTLA (lb), which in turn is an efficient substrate for Phase II clearance through... 

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