both nifedipine and diltiazem significantly altered the hemodynamics, but to a different extent in the two groups of patients. The heart-transplant patients showed ...
Short-term effects of calcium antagonists on hemodynamics and cyclosporine pharmacokinetics in heart-transplant and kidney-transplant patients Effects of two calcium antagonists on hemodynamics and on cydosporine pharmacokinetics were studied in eight transplant patients (four heart-transplant and four kidney-transplant patients) by use of a singleblind, randomized, crossover, and placebo-controlled design. Patients received, at least 1 week apart, either 90 mg diltiaz,em, 20 mg nifedipine (in tablet form), or placebo, given 1 hour before cydosporine. Cydosporine and its main metabolite (metabolite 17) were measured in plasma (separated at 25° C) by use of HPLC. Both calcium antagonists tended to increase absorption rate and elimination rate, but none of the pharmacokinetic parameters of cydosporine were significantly altered. Moreover, the area under the curve of plasma concentrations of metabolite 17 did not change. On the other hand, both nifedipine and diltiazem significantly altered the hemodynamics, but to a different extent in the two groups of patients. The heart-transplant patients showed larger decreases in systolic and diastolic blood pressure than the kidney-transplant patients after administration of both nifedipine and diltiazem, but they showed smaller increases in cardiac index and heart rate with nifedipine. In contrast, diltiazem caused small decreases in heart rate and cardiac index in heart-transplant patients and small increases in heart rate and cardiac index in kidney-transplant patients. We conclude that a single dose of either nifedipine or diltiaz,em does not affect, to a clinically significant extent, the pharmacokinetics of cydosporine. In addition, heart-transplant patients show different hemodynamic responses to these two calcium antagonists than the responses shown by kidney-transplant patients, probably because of cardiac denervation. (CLIN PHARMACOL THER 1989;46:657-67.)
L. F. Roy, MD,a D. S. East, PhD, F. M. Browning, BS, D. Shaw, BS, H. Leenen, MD, PhDb R. I. Ogilvie, MD, C. Cardella, MD, and F. Toronto, Ontario, Canada
Cyclosporine is now widely used for immunosuppression, particularly in the setting of transplantation. However, this drug has several adverse effects, the most important of which is renal dysfunction.' In
From the Divisions of Clinical Pharmacology and Nephrology, Department of Medicine, Toronto Western Hospital, and the Departments of Medicine and Pharmacology, University of Toronto. Supported by grants in aid from Sandoz Canada and Nordic Laboratories. Received for publication April 4, 1989; accepted Aug. 8, 1989. Reprint requests: F. H. H. Leenen, MD, PhD, FRCPC, Hypertension Unit, University of Ottawa Heart Institute, 1053 Carling Ave., Ottawa, Ontario, Canada KlY 4E9. 'Present address: Hopital St-Luc, Andre-Viallet Clinical Research Centre, 264 Rene-Levesque Blvd. East, Montreal, Quebec, Canada H2X IPI. bCareer Investigator of the Heart and Stroke Foundation of Ontario.
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the initial treatment period this is secondary to hemodynamic changes at a preglomerular level, possibly mediated by cyclosporine effects on prostaglandins''' or on the renin-angiotensin system.56 This vasculotoxic phase can be reversed by a decrease in the dosage or by discontinuation of cyclosporine. After a few months, interstitial fibrosis and tubular atrophy may develop' and the renal dysfunction may becomeat least partlyirreversible. One approach to minimize this adverse effect involves regular measurement of the blood concentrations of cyclosporine and adjustment of the dose of cyclosporine. On the other hand, in humans who receive immunosuppression treatment with cyclosporine, diltiazem may prevent early renal dysfunction after renal transplantation," particularly if the graft itself is saved in a solution that contains diltiazem.m Nephroprotection may be related to the inhibitory effect of both verapamil and diltiazem on cy-
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Roy et al.
Table I. Pharmacokinetic parameters for cyclosporine and its principal metabolite, metabolite 17, with and without concomitant calcium antagonist administration Cyclosporine (n = 8)
Predose plasma cyclosporine Placebo Diltiazem Nifedipine
(ng I ml)
(hr')
±_ 48 207 ± 30 188 ± 67
0.71 ± 0.23 1.00 ± 0.35 1.16 -± 0.33
136
C,, (hr)
(ng I ml)
-± 0.5 2.8 ± 0.3 2.4 ± 0.8
652 7-t. 111 599 -± 169 632 ± 151
3.1
km
(hr0.21 -± 0.03 0.26 ± 0.30 0.25 ± 0.05
AUC
(mgILIhr) 4.01 ± 0.56 3.47 -± 0.55 3.15 ± 0.61
Data are presented as mean values ± SEM. lc, Absorption rate constant; time of maximum concentration; Cn,ax, maximum concentration; lc,o, elimination rate constant; AUC, area under the plasma concentrationtime curve; AUCp/AUC,, ratio of plasma AUC of cyclosporine (parent) over the plasma AUC of metabolite 17.
closporine uptake by isolated proximal tubular cells in vitro." However, in addition to this pharmacodynamic interaction between diltiazem and cyclosporine, a potentially adverse pharmacokinetic interaction has been described. During concomitant therapy with diltiazem, blood concentrations of cyclosporine were reported to increase within two days, and the dose of cyclosporine required to maintain previous blood levels was decreased.9"2-14 However, these studies represent only case reports or abstracts, and cyclosporine levels were assessed by polyclonal radioimmunoassay methods that measured both parent compound and metabolites, with the exception of the study by Wagner et al.,' which evaluated the long-term interaction by both HPLC and radioimmunoassay. To obtain a better understanding of the effects of different calcium antagonists on cyclosporine kinetics and actions, the short-term effects of single doses of two calcium antagonists were compared with regard to their effects on systemic hemodynamics and the pharmacokinetics of cyclosporine in transplant patients who were receiving long-term maintenance cyclosporine therapy. Because diltiazem and nifedipine act at different cellular receptor sites," and may therefore have different effects on cyclosporine kinetics, both nifedipine (slow-release 20 mg) and diltiazem (90 mg) were studied. As a secondary objective, kidney-transplant and heart-transplant patients were compared because the hemodynamic effects of calcium antagonists are likely to differ in these two types of patients.
METHODS Subjects. Four men who had received heart trans2 kg, plants (52 6 years, 166 -± 3 cm, 82 mean -± SEM) and four men who had received kidney transplants (38 -± 3 years, 169 ± 3 cm, 77 ± 2 kg, mean -± SEM) participated in the study. To avoid the LE_
early changes in pharmacokinetics of cyclosporine observed in the first few weeks," each patient was studied at least 3 months after his transplant surgery. They were studied at steady state, that is, at least 1 week after the last change in cyclosporine dose, with stable heart function, and with a stable serum creatinine (
