Dihydropyridines metabolism

Miniscalco A,Lundahl J, GunnarRegardh C, Edgar B, Eriksson UG. 1992. Inhibition of dihydropyridine metabolism in rat and human liver microsomes by flavonoids found in grapefruit juice. J. Pharmacol. Exp. Ther. 261 1195-99... 

A synthetic neurotoxin that causes parkinsonism in human and nonhuman primates, mice, gold fish, and dogs. MPTP is inert but metabolized by MAO-B to the neurotoxin MPP+ (1,2-dihydropyridine ion). This neurotoxin causes depletion of dopamine and degeneration of nigrostriatal dopamine neurons similar to what is observed in Parkinson s disease. 

Hypertension Calcium channel blockers ACE inhibitors ARBs Diltiazem, verapamil inhibit CSA/TAC metabolism Dihydropyridines may potentiate CSA-gingival hyperplasia May exacerbate hyperkalemia monitor K+, SCr to assess for renal allograft vascular disease may be useful in posttranplant erythrocytosis (hematocrit greater than 55%)... 

Since the pyridine derivatives obtained as metabolic products of SKF 24260 are inactive (42), the importance of the dihydropyridine structure is clear. 

N. Ogawa, T. Hirose, K. Fukushima, T. Suwa, T. Satoh, GSH-Independent Denitration of the Nitrate Ester of a Dihydropyridine Derivative in Rabbit Hepatic Cytosol , Biochem. Pharmacol. 1995, 49, 141 -146 N. Ogawa, T. Flirose, K. Fukushima, T. Suwa, T. Satoh, Metabolism of a Nitrate Ester, Dihydropyridine Derivative in Rabbit Hepatic Microsomes and Cytosol , Xenobiotica 1995, 25, 283-290. 

Amlodipine shows a preference for binding vascular smooth muscle cells over cardiac muscle cells, thus acting as a peripheral arterial vasodilator (Pfizer, Inc. 2005). Like most other CCB dihydropyridines, amlodipine is highly protein bound and heavily metabolized. In contrast to felodipine, this compound is not influenced by grapefruit juice and appears to show fewer drug-drug interactions. 

Ethionamide is well absorbed foUowtng oral administration. It is rapidly and widely distributed to all body tissues and fluids, including the cerebrospinal fluid. Metabolism of ethionamide is extensive, and several dihydropyridine metabolites are produced. Less than 1% of the drug is eliminated in the urine unchanged. 

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... 

The dihydropyridine class of calcium channel blockers undergoes extensive first-pass oxidation by CYP3A isoforms to their pyridine metabolites, and several studies have shown that inducers and inhibitors of these P450s decrease and increase the blood concentrations of the active dihydropyridine structures, respectively (51). The calcium channel blockers verapamil and diltiazem are unrelated structures that also undergo significant metabolism by cytochromes... 

Lercanidipine (Fig. 7.10) is one of the last dihydropyridines introduced into the market. Its high lipophilicity explains its long duration of action. Lercanidipine is extensively metabolized in the liver after oral administration, and is then retained by vascular cells to achieve a sustained duration of action. It is used in the treatment of hypertension and angina. like lacidipine, its smooth onset of action... 

There are two groups dihydropyridines and diltiazem/verapamil. Both groups are metabolized by the CYP3A family of isoenzymes (especially CYP3A4), which are the sites of many of the pharmacokinetic interactions involving this class. Some drugs are substrates for P-gp. 

FLUCONAZOLE, ITRACONAZOLE, KETOCONAZOLE, POSACONAZOLE, VORICONAZOLE CALCIUM CHANNEL BLOCKERS Plasma concentrations of dihydropyridine calcium channel blockers are t by fluconazole, itraconazole and ketoconazole. Risk of t verapamil levels with ketoconazole and itraconazole. Itraconazole and possibly posaconazole may t diltiazem levels The azoles are potent inhibitors of CYP3A4 isoenzymes, which metabolize calcium channel blockers. They also inhibit CYP2C9-mediated metabolism of verapamil. Ketoconazole and itraconazole both inhibit intestinal P-gp, which may t bioavailability of verapamil. Diltiazem is mainly a substrate of CYP3A5 and CYP3A5P1, which are inhibited by itraconazole. 75% of the metabolism of diltiazem occurs in the liver and the rest in the intestine. Diltiazem is a substrate of P-gp (also an inhibitor but unlikely to be significant at therapeutic doses), which is inhibited by itraconazole, resulting in t bioavailability of diltiazem Monitor PR, BP and ECG, and warn patents to watch for symptoms/signs of heart failure... 

The diverse nature of these effects is illustrated by recounting the experience of clinical pharmacologists who studied the pharmacokinetics of felodipine, a dihydropyridine calcium channel antagonist (14). They designed a study to test the effects of ethanol on felodipine metabolism. To mask the flavor of ethanol from the subjects, they tested a variety of fruit juices, selecting double-strength grapefruit juice prepared from frozen concentrate as most effective. 

The effects of antihypertensive agents have been evaluated in patients taking ciclosporin. Collectively, dihydropyridine calcium channel blockers that do not affect ciclosporin blood concentrations substantially or at all (felodipine, isradipine, and nifedipine) are usually considered to be the drugs of choice. However, the risk of gingival hyperplasia with nifedipine, which ciclosporin also causes, should be borne in mind. Combination therapy with angiotensin-converting enzyme inhibitors or beta-blockers, or the use of other calcium channel blockers (verapamil or diltiazem) should also be considered, but careful monitoring of ciclosporin blood concentrations is recommended with the latter because they inhibit ciclosporin metabolism. 

Hypertension Calcium channel blockers Diltiazem, verapamil inhibit CSA/TAC metabolism Dihydropyridines may potentiate CSA-gingival hyperplasia... 

Marazano [62] has proposed a metabolic scheme relating the production of the manzamines to the biosynthetic origin of sarain A [63] and halicyclamine A [64], These compounds share the dihydropyridinium salt and dihydropyridine structural motifs. 

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