Cytochrome P450 renal

H)2-D3 is a weak agonist and must be modified by hydroxylation at position Cj for full biologic activity. This is accomplished in mitochondria of the renal proximal convoluted tubule by a three-component monooxygenase reaction that requires NADPFl, Mg, molecular oxygen, and at least three enzymes (1) a flavoprotein, renal ferredoxin reductase (2) an iron sulfur protein, renal ferredoxin and (3) cytochrome P450. This system produces l,25(OH)2-D3, which is the most potent namrally occurring metabolite of vitamin D. 

Nateglinide (N) Starlix 60, 120 120 with meals 120 with meals NA 120 mg three times a day Up to 4 hours Metabolized by cytochrome P450 (CYP450) 2C9 and 3A4to weakly active metabolites renally eliminated... 

Dosage adjustment - Consider a starting dose of 25 mg in the following patients Older than 65 years of age, hepatic impairment, severe renal impairment, and concomitant use of potent cytochrome P450 3A4 inhibitors (eg, erythromycin, ketoconazole, itraconazole, saquinavir). 

Metabollsm/Excretion— Itraconazole is metabolized by the cytochrome P450 3A4 to several metabolites including the major metabolite hydroxyitraconazole. Fecal excretion of the parent drug varies between 3% and 18% of the dose. Renal excretion of the parent drug is less than 0.03% of the dose. Itraconazole is not removed by hemodialysis. 

However, in patients with renal failure there is a strange and currently unexplained observation in relation to non-renal clearance. If this is measured for some compounds it also is found to be depressed even though it is the kidney that is diseased and not the liver The picture becomes a little clearer if the same non-renal (presumed hepatic) clearance is measured again in patients after renal dialysis when the hepatic clearance has been found to have risen to control values. Recent animal experiments have demonstrated that the circulating inhibitor of hepatic cytochrome P450 may be parathyroid hormone. Parathyroidectomy of rats with chronic renal failure prevented the reduction in liver cytochrome activity (see Michaud et al., 2006). 

Michaud J, Naud J, Chouinard J, Desy F, Leblond FA, Desbiens K et al. Role of parathyroid hormone in the downregulation of liver cytochrome P450 in chronic renal failure. J Am Soc Nephrol 2006 17 3041-8. 

They have a low incidence of adverse reactions and the reactions that occur are generally mild. Rapid intravenous infusion of H2 antagonists may cause bradycardia. Cimetidine is more inclined to cross the blood-brain barrier and CNS effects such as somnolence and confusion have been described, especially in the elderly and in patients with impaired renal function. Cimetidine in high doses, as the only one of its class, has antiandrogenic effects which could be explained by an increase of prolactin secretion, binding to androgen receptors and inhibition the cytochrome P450 mediated hydroxylation of estradiol. 

A. Diazepam is metabolized in the liver by CYP3A4 and CYP2C19 efavirenz inhibits both of these isozymes and is likely to increase plasma levels of diazepam. Diazepam is almost completely converted to inactive metabolites therefore, renal elimination is not much of a concern. Lamivudine may produce fatigue as a side effect but does not potentiate the depressant activity of diazepam. Zidovudine does not induce cytochrome P450 activity, and diazepam does not have to be converted to an active form for sedative activity. 

Memantine is not a major substrate for hepatic cytochrome P450 isoenzymes and has not been shown to significantly inhibit or induce these enzymes. However, memantine is partially excreted by renal tubular secretion. Thus, concomitant use of other medications that use the same renal system (i.e., triampterene, hydrochlorothiazide, digoxin, cimetidine, ranitidine, metformin, and quinidine) may affect plasma levels of both drugs (Namenda 2005). Memantine should not be used in combination with other NMDA receptor antagonists, such as amantadine or dextromethorphan, because these combinations have not been formally studied. The clearance of memantine can be reduced when the urine is alkalinized, such as with the concomitant use of sodium bicarbonate or carbonic anhy-... 

No clinical signs or changes in mortality were found in a cohort of exposed workers. In rats, 1,4-dioxane produces degenerative and necrotic changes in liver and renal tubules. High doses can significantly increase the total hepatic cytochrome P450 content. 

Speerschneider, P. Dekant, W. (1995) Renal tumorigenicity of 1,1-dichloroethene in mice the role of male-specific expression of cytochrome P450 2E1 in the renal bioactivation of 1,1-dichloroethene. Toxicol, appl. Pharmacol., 130, 48-56... 

Renal and hepatic toxicity has been described follow ing human accidental poisonings and experimental exposure of rats and mice. In rats, hepatic cytochrome P450 content, particularly of CYP2B1, and the activities of certain conjugation enzymes are increased upon inhalation exposure to meta- y ex Q. Although xylenes have been studied extensively, there is no confirmed evidence of genetic activity for any of the isomers. 

Pentachloroethane given to rats by gavage during a two-year study caused chronic, diffuse kidney inflammation and renal papilla mineralization. A single dose also reduced hepatic cytochrome P450 content and microsomal epoxide hydrolase activities. Inhalation exposure of rabbits to pentachloroethane decreased their total antibody titres (lARC, 1986). 

The mean elimination half-life is about 6 h. The O-demethylation of tramadol to Ml, the main analgesic effective metabolite, is catalyzed by cytochrome P450 (CYP) 2D6, whereas A-demeth-ylation to M2 is catalyzed by CYP2B6 and CYP3A4. The wide variability in the pharmacokinetic properties of tramadol can partly be ascribed to CYP polymorphism. O- and A-demethylation of tramadol as well as renal elimination are stereoselective.56... 

Rhabdomyolysis in a stable renal transplant recipient was attributed to the presence of red yeast rice (Monascus purpureus) in a herbal mixture (116). The condition resolved when he stopped taking the product. Rice fermented with red yeast contains several types of mevinic acids, including monacolin-K, which is identical to lovas-tatin. The authors postulated that the interaction of ciclosporin with these compounds through cytochrome P450 had resulted in the adverse effect. Transplant recipients must be cautioned against using herbal products to lower their lipid concentrations, in order to prevent such complications. 

The roles of leukotrienes and cytochrome P450 products in the human kidney are currently speculative. Recently, the 5,6-epoxide has been shown to be a powerful vasodilator in animal experiments. Another recent discovery is that free radicals attack arachidonic acid-containing phospholipids to yield an 8-ep/-PGF2[J that has powerful thromboxane-like properties. Synthesis is not blocked by COX inhibitors but can be blocked by antioxidants. This vasoconstrictor, which is present in humans, is thought to be another important mediator causing renal failure in the hepatorenal syndrome. 

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