Felodipine metabolism

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. 

An additional example of a bioavailability-predicted absorption plot is shown for a series of calcium antagonists (Fig. 19.8). Again there is considerable scatter in the data, and the four compounds - felodipine, nisoldipine, diltiazem, and verapamil -are predicted to be much better absorbed than was actually observed. Some of these compounds are known to undergo rapid first-pass metabolic clearance, and are also P-gp inhibitors or substrates (diltiazem and felodipine are P-gp substrates nicardipine and nitrendipine are P-gp inhibitors [25] verapamil is a P-gp inhibitor), and this might contribute to the scatter obtained in the graph. 

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. 

Felodipine 15-20% 2-5 hours (oral) 11-16 > 99% bound to plasma proteins extensively metabolized. 

Wang SX, Sutfm TA, Baarnhielm C, et al. Contribution of the intestine to the first-pass metabolism of felodipine in the rat. J Pharmacol Exp Ther 1989 250 632-636. 

CALCIUM CHANNEL BLOCKERS MACROLIDES t plasma concentrations of felodipine when co-administered with erythromycin cases of adverse effects of verapamil (bradycardia and 1 BP) with both erythromycin and clarithromycin Erythromycin inhibits CYP3A4-mediated metabolism of felodipine and verapamil. Clarithromycin and erythromycin inhibit intestinal P-gp, which may t the bioavailability of verapamil Monitor PR and BP closely watch for bradycardia and 1 BP. Consider reducing the dose of calcium channel blocker during macrolide therapy... 

CALCIUM CHANNEL BLOCKERS TACROLIMUS Plasma concentrations of tacrolimus are t when given with diltiazem, felodipine or nifedipine however, they appear to protect renal function Uncertain, but presumed to be due to inhibition of CYP3A4-mediated tacrolimus metabolism Watch for side-effects of tacrolimus monitor ECG, blood count and renal and hepatic function... 

CALCIUM CHANNEL BLOCKERS CARBAMAZEPINE 1. Diltiazem and verapamil T plasma concentrations of carbamazepine (cases of toxicity) 2.1 plasma concentrations of felodipine, nifedipine and possibly nimodipine and nisoldipine 1. Diltiazem and verapamil inhibit CYP3A4-mediated metabolism of carbamazepine. They also inhibit intestinal P-gp, which may t the bioavailability of carbamazepine 2. Carbamazepine, in turn, induces CYP3A4, which metabolizes calcium channel blockers 1. Monitor carbamazepine levels when initiating calcium channel blockers, particularly diltiazem and verapamil 2. Monitor PR and BP closely watch for T BP when starting carbamazepine in patients already on calcium channel blockers... 

CANNABIS DILTIAZEM, FELODIPINE, NIFEDIPINE, NIMODIPINE, NISOLDIPINE Unpredictable changes in plasma concentration. Risk of toxicity or therapeutic failure, particularly of drugs with a narrow therapeutic index Induction or inhibition of CYP3A4-mediated metabolism by cannabis. It is not yet known whether the effects are dependent on the degree of cannabis consumption Be aware. Watch for signs of toxicity, especially when cannabis use abruptly changes... 

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. 

---