Antihypertensive effect of amlodipine and lack of interference with cyclosporine metabolism in renal transplant recipients.

Abstract

The catabolism of various calcium channel blockers through cytochrome P-450 is heterogeneous and may be modified by concomitant use of cyclosporin A. In an open study we investigated the antihypertensive effect and clinical tolerance of the dihydropyridine amlodipine and its effects on cyclosporine kinetics in stable hypertensive renal transplant recipients not taking corticosteroids. Ten adult hypertensive patients grafted for 21.4±8.9 months and well stabilized with normal renal function were included in the study. Renal artery stenosis was ruled out by normal Doppler echography. After 2 weeks of placebo, amlodipine was started at a daily dose of 5 mg. The dose was then adjusted to 10 mg if necessary. Blood and urine chemistries and whole-blood cyclosporine trough levels were measured weekly. Cyclosporine kinetics were determined on a hourly basis before amlodipine administration and after 4 weeks of treatment. Normal blood pressure was obtained with the use of 5 mg/d amlodipine in 7 patients and 10 mg/d in 3, diastolic blood pressure decreasing from I n the transplanted patient treated with cyclosporine, all drugs that may modulate cytochrome P-450 activities can induce deleterious effects. 13Interference with cyclosporine metabolism induces either an increase of blood cyclosporine levels, and consequently potentiation of cyclosporine nephrotoxicity, or a decrease of cyclosporine levels, with a risk of acute rejection. Among the various drugs that interfere with cyclosporine metabolism are some members of the calcium channel blocker family, which are particularly efficient in treating the hypertension that occurs in more than 80% of transplant recipients. Diltiazem, 4 verapamil, 5 and nicardipine 67 increase cyclosporine levels by competitive inhibition of cytochrome P-450 activities, 8 whereas other calcium channel blockers, such as nifedipine, 9 nitrendipine, 10 and isradipine, 11 do not interact with cyclosporine significantly.We undertook the present study in the hypertensive renal transplanted patient on cyclosporine without cor- 98.7±3.8 to 81.3±9.1 mm Hg (/ > =.0007). Heart rate slightly increased by 10% (P<.02). The drug was well tolerated, and only minor ankle edema was found in 3 patients. Cyclosporine doses were not modified and cyclosporine levels remained unchanged throughout the study. Cyclosporine kinetic parameters were not significantly different at the beginning and end of the study. Bioequivalence was demonstrated indicating that cyclosporine biotransformation was not altered by the concomitant administration of amlodipine. We conclude that amlodipine at the dosage of 5 to 10 mg/d is an efficient calcium channel blocker in hypertensive renal transplant recipients treated with cyclosporine without corticosteroids. Moreover, amlodipine does not interfere with cyclosporine diffusion and metabolism. 12 Our goals were (1) to test the antihypertensive effect and tolerance of the drug given as unique antihypertensive therapy and (2) to detect any change in cyclosporine kinetics in the part...

Amlodipine once-daily in systemic hypertension

“…However, treatment with certain calcium channel blockers such as nicardipine, diltiazem or verapramil results in a marked increase in blood cyclosporine levels [10]. Our observations and a study in adults [19] indicate that amlodipine does not interfere with the metabolism of cyclosporine but in some patients amlodipine slightly increases cyclosporine levels [14]. Calcium antagonists [17] and cyclosporine [10] may induce gum overgrowth.…”

Calcium channel blockers: pharmacology and place in therapy of pediatric hypertension

“…However, in at least one adult study, amlodipine was reported to increase cyclosporine levels by 25-40% [82]. Other studies have not confirmed this finding [83]. Diltiazem is also known to increase levels of both cyclosporine and tacrolimus [84][85][86][87], an effect that has been utilized by some investigators to reduce the amount of cyclosporine administered [84].…”

Negligible pharmacokinetic interaction between oral DA-8159, a new erectogenic, and amlodipine in rats

“…This suggests that the CYP3A1/2 amounts are sufficient simultaneously to metabolize the amlodipine and DA-8159 at the doses used in the present study. Almost no drug interaction between amlodipine and cyclosporine A, mainly metabolized via CYP3A4 in humans [24], was also reported in renal transplant recipients [25]. Human CYP3A4 and rat CYP3A1 have 73% homology [26].…”