Nifedipine metabolism

McFadden JP, Pantin JE, Parkes AV, et al. Cyclosporin decreases nifedipine metabolism. BMJ 1989 299 1224. 

Nifedipine is absorbed efficiently on oral or buccal admin-hlraliun. A sub.siunlial amount (00%) is protein bound. Sys-emic availability of an oral dose of the drug may be approxi-malcly 6.S%. Two inactive metabolites are the major products of nifedipine metabolism and are found in equilib-liam with each other (Fig. 19-9). Only a trace of unchanged tifedipinc is found in the urine." ... 

To assess in a single session the incidence of the poor-metabolizer phenotypes for sparteine and mephenytoin, and the variability in nifedipine metabolism, in a Dutch population of 172 subjects [20]. A 7.4% incidence of poor metabolizers of sparteine was detected, which is quite similar to that found in other Caucasian populations. For mephenytoin 2.3% of this population was found to poorly metabolize it to para-hydroxymephenytoin. In a similar study in 130 healthy subjects a cocktail of phenytoin, sparteine and nifedipine was administered [22], The results of this study for nifedipine have been presented in Fig. 1, whereas a similar extent of variability in the plasma kinetic (AUC) for phenytoin was observed. Correlations between relevant kinetic and metabolic parameters of the three probe drags were all low and non-significant. None of the data of nifedipine and phenytoin were different between extensive and poor metabolizers of sparteine. Thus the major oxidative metabolic pathways of nifedipine, sparteine and phenytoin are not related to each other. The three compounds can in principle be used... 

To assess selectivity in the inducing and inhibiting effects of environmental factors (for example, dmg treatment) on the activity of the different P-450 enzymes. In one of such smdies, nifedipine, sparteine, mephenytoin and antipyrine were administered simultaneously to 15 healthy subjects, including four poor metabohzers of sparteine and four poor metabolizers of mephenytoin [6], They received the cocktail on three different occasions without pretreatment, after pentobarbital pretreatment and together with cimetidine. Concentrations of nifedipine, its pyridine metabolite, and of sparteine and its dehydro metabolite were measured in the plasma nifedipine metabohtes, sparteine, dehydrosparteine, 4-hydroxymephenytoin, antipyrine and its three major metabohtes were all measured in urine. The kinetic parameters obtained clearly indicated that nifedipine metabolism is very sensitive to pentobarbital induction (Fig. 4), whereas antipyrine metabolism is sensitive only to a moderate degree and sparteine metabolism is unaffected. Cimetidine inhibited the metabohc clearance of all three compounds to a similar extent and also inhibited renal clearance of sparteine, most likely at the level of tubular secretion. Urinary excretion of 4-... 

Lee SJ, van der Heiden IP, Goldstein JA, van Schaik RH (2007) A new CYP3A5 variant, CY-P3A5 11, is shown to be defective in nifedipine metabolism in a recombinant cDNA expression system. Drug Metab Dispos 35 67-71... 

The H2RAs are generally well tolerated. The most common adverse effects are headache, somnolence, fatigue, dizziness, and either constipation or diarrhea. Cimetidine may inhibit the metabolism of theophylline, warfarin, phenytoin, nifedipine, and propranolol, among other drugs. 

Of all N Rs involved in xenobiotics metabolism induction, PX R is the most prominent one. PXR functions as a xenobiotic sensor and is activated by a large variety of chemically diverse compounds, for example lovastatin, nifedipine, rifampicin, SR12813, troglitazone or hyperforin (Chart 14.3), many of them standard therapeutic agents for common diseases [20-25]. 

Rifampin is known to induce the hepatic microsomal enzymes that metabolize various drugs such as acetaminophen, oral anticoagulants, barbiturates, benzodiazepines, beta blockers, chloramphenicol, clofibrate, oral contraceptives, corticosteroids, cyclosporine, disopyramide, estrogens, hydantoins, mexiletine, quinidine, sulfones, sulfonylureas, theophyllines, tocainide, verapamil, digoxin, enalapril, morphine, nifedipine, ondansetron, progestins, protease inhibitors, buspirone, delavirdine, doxycycline, fluoroquinolones, losartan, macrolides, sulfonylureas, tacrolimus, thyroid hormones, TCAs, zolpidem, zidovudine, and ketoconazole. The therapeutic effects of these drugs may be decreased. 

T Pancreatic insulin release Metformin Peripheral insulin sensitivity hepatic glucose output/production i intestinal glucose absorption Dose Ist-line (naive pts), 1.25/250 mg PO daily-bid 2nd-line, 2.5/500 mg or 5/500 mg bid (max 20/2000 mg) take w/ meals, slowly T dose hold before 48 h after ionic contrast media Caution [C, -] Contra SCr >1.4 mg/dL in females or >1.5 mg/dL in males hypoxemic conditions (sepsis, recent MI) alcoholism metabolic acidosis liver Dz Disp Tabs SE HA, hypoglycemia, lactic acidosis, anorexia, N/V, rash Additional Interactions T Effects W/ amiloride, ciprofloxacin cimetidine, digoxin, miconazole, morphine, nifedipine, procainamide, quinidine, quinine, ranitidine, triamterene,... 

Nifedipine is a dihydropyridine calcium channel modulator, often used in the treatment of hypertension and angina. CYP3A4, with a minor contribution from CYP3A5, is the principal enzyme involved in the metabolism of nifedipine (81). Smith et al. examined the effect of St. John s wort (900mg/day... 

Holtbecker N, Fromm MF, Kroemer HK, Ohnhaus EE, Heidemann H. The nifedipine-rifampin interaction. Evidence for induction of gut wall metabolism. Drug Metab Dispos 1996 24(10) 1121-1123. 

Grapefruit juice Coadministration of nifedipine with grapefruit juice results in up to a twofold increase in AUC and Cmax) due to inhibition of CYP3A4-related first-pass metabolism. This effect of grapefruit juice may last for at least three days. Administration of nifedipine with grapefruit juice is to be avoided... 

Coadministration of nifedipine and grapefruit juice resulted in an approximately twofold increase in nifedipine area under the curve (AUC) and Cmax with no change in half-life. The increased plasma concentrations are most likely due to the inhibition of CYP3A4-related first-pass metabolism. 

The sublingual surface area is relatively small but has a rich blood supply. The major advantage of this route is avoidance of intestinal destruction and hepatic first pass metabolism. However, absorption can be highly variable critical factors are the residence time of the drug in the mouth and saliva flow. Premature swallowing or excessive saliva production preclude efficient absorption. Nitroglycerin, nifedipine, propranolol, and buprenorphine are all available as sublingual preparations. Rectal... 

Verapamil, diltiazem, and perhaps nicardipine (but not nifedipine) inhibit hepatic drug-metabolizing enzymes. Metabolism of diltiazem, nifedipine, verapamil, and probably other calcium channel blockers subject to induction and inhibition. 

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