Renal CYPs

Zhou Y, Lin S, Chang HH, Du J, Dong Z, Dorrance AM, Brands MW, Wang MH (2005) Gender differences of renal CYP-derived eicosanoid synthesis in rats fed a high-fat diet. Am J Hypertens 18 530 537... 

HU, a freely water-soluble molecule, crosses the intestinal wall and other cells by passive diffusion [5, 6], and tissue concentration of HU rapidly matches its blood concentration [7]. The oral bioavailability of HU is nearly complete and hence therapeutically simple to administrate. HU undergoes biotransformation and is converted into urea by a yet-to-be identified hepatic P450 monooxygenase (CYP) enzyme [8, 9], Elimination of HU and its metabolites involves both renal and non-renal mechanisms. 

Kidney failure not only decreases renal clearance of nicotine and cotinine, but also metabolic clearance of nicotine (Molander et al. 2000). Metabolic clearance of nicotine is reduced by 50% in subjects with severe renal impairment compared to healthy subjects. It is speculated that accumulation of uremic toxins may inhibit CYP2A6 activity or downregulate CYP2A6 expression in liver. Hepatic metabolism of several drugs is reduced in kidney failure, mainly via downregulation of CYP enzymes and/or inhibition of transporters (Nolin et al. 2003). 

The prolonged half-lives occur in individuals who are genetically different in CYP 2D6 or who have significant hepatic, renal, or left ventricular cardiac dysfunction. TCAs are metabolized in the liver by three pathways ... 

Maximal plasma concentrations occur 2 to 3 hours after oral administration of reboxetine (178). Reboxetine has linear pharmacokinetics over its clinically relevant dosing range and a half-life of approximately 12 hours. For this latter reason, a twice a day, equally divided dosing schedule was used during clinical trial development. Its clearance is reduced and half-life becomes longer as a function of advanced age (mean = 81 years of age) and renal and hepatic impairment ( 178, 322, 323). Reboxetine is principally metabolized by CYP 3A3/4 such that its dose should be reduced when used in combination with drugs that are substantial inhibitors of CYP (e.g., certain azole antifungals, certain macrolide antibiotics). Reboxetine itself, however, does not cause detectable inhibition of CYP 3A3/4 based on formal in vivo pharmacokinetic interaction studies as well as its own linear pharmacokinetics. 

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... 

While renal contribution to overall metabolism is less than hepatic contribution, renal metabolism is of clinical importance. The kidney, in particular the renal cortex, contains many of the same metabolic enzymes found in the liver, including CYPs. Serum creatinine and creatinine clearance are the typical methods used to assess renal function, although 24-hour urine collection can also be used. These are reliable indicators of renal clearance. 

Sitaxsentan is a potent and selective agent which inhibits ET-1 binding to ETA receptors (IC50 = 1.4 nM), while being essentially inactive at ETB receptors (IC50 = 9.8 pM).23 In the clinic, it was found to have excellent oral bioavailability (70-100%) and a terminal elimination half-life of 10 h, and is administered as a once daily 100 mg dose. It is highly protein bound in plasma (> 99%) and extensively metabolized in the liver to inactive metabolites, predominantly by CYPs 2C9 and 3A4. Excretion is 50 60% renal, with the balance in the feces.25 Sitaxsentan inhibits CYP 2C9, and was observed to increase exposure to warfarin by over twofold. The use of cyclosporine A is also contraindicated, but no interactions were observed with sildenafil.15 Sitaxsentan was well tolerated in trials, with only minor side effects reported. Reversible liver enzyme abnormalities were also observed, but less frequently than with bosentan.15 25... 

Metabolized by CYP 2C8 and 2C9 to inactwe metabolites that are renally eraeled... 

Furosemide is eliminated in equal portions by renal and non-renal (glucuronidation) routes. Its half-life is prolonged in renal failure, but hepatic failure has little effect, Bumetanide and torasemide are eliminated via CYP isoenzymes and so their half-life is affected by hepatic disease more than renal disease. They are known to cause thrombocytopenia (hut decrease activity of oral anticoagulants), ototoxicity and nephrotoxicity. 

Naratriptan is metabolized by the CYP isoenzymes and MAO-A enzymes, and is also subject to renal elimination. 

The elimination of linezolid is by non-renal means (and does not involve CYP isoenzymes). It has weak MAOI activity. Myelosuppression, both dose- and time-dependent, occurs in 2-10% of patients with therapeutic doses. Linezolid interacts with serotonergic and adrenergic drugs. 

The many drug interactions described with cimetidine are largely attributable to inhibition of CYP isozymes or renal clearance of other drugs. Cimetidine also reduces hepatic blood flow and so can, for example, reduce the clearance of lidocaine. In the kidneys cimetidine interferes with the tubular excretion of procainamide and quinidine. Both effects are small, and the long list of drugs for which interference is demonstrable (Table 1) is out of all proportion to the number for which interference is of chnical significance. 

Phenobarbital is metabolized by CyP 2C19 to p-hydroxy-phenobarbital, which is largely excreted as the glucuronide (by UGT). When renal and hepatic function are decreased, patients experience decreased clearance of the drug. Alcohol, carbamazepine, other barbiturates, and rifampin induce oxidative enzymes (CyP 2C19 and 2C9) this induction results in increased metabolism of phenytoin, reduced serum concentration of phenobarbital, and a reduced pharmaco-... 

Disopyramide is metabolized to nordisopyramide (monodealkylated) by the action of CyP 2D6 nordisopyramide has antiarrhythmic activity approximately 25% that of disopyramide. Under normal circumstances, nordisopyramide accumulates to concentrations ranging from 0.2 to l.Opg/mL, and the compound does not accumulate out of proportion to disopyramide in situations of reduced hepatic or renal function. Therefore little additional therapeutic information is gained by monitoring nordisopyramide. 

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