A drug interaction study between ticlopidine and cyclosporin in heart transplant recipients.
OBJECTIVE
Previous uncontrolled studies have suggested an interaction between ticlopidine, a major antiplatelet agent, and cyclosporin in heart- and kidney-transplant recipients. The aims of this study were to examine in a randomised, double-blind fashion, the possible interaction between cyclosporin A and ticlopidine (250 mg per day) and the tolerability of this combination in heart-transplant recipients.


METHODS
Twenty heart-transplant recipients were randomised into either a treated or a placebo group. Blood samples were drawn for time-course evaluation of cyclosporin blood levels over a period of 12 h, following the morning intake of cyclosporin and, for platelet aggregation studies, before and after 14 days of ticlopidine administration. Twenty four-hour urine samples were collected for 6-beta-hydroxycortisol measurements, before and after 14 days of ticlopidine.


RESULTS
Although given at half the recommended daily dosage, ticlopidine significantly reduced platelet aggregation. Pharmacokinetic parameters indicate that the bioavailability of cyclosporin A was not significantly modified by ticlopidine. However, one patient in the ticlopidine group was withdrawn because of a major fall in cyclosporin blood level within 3 days of treatment. Urinary excretion of 6-beta-hydroxycortisol was augmented after treatment in the ticlopidine group compared with the placebo group, suggesting that induction of drug metabolism might have occurred. Data also show quite a large intra-individual variability in cyclosporin bioavailability in the placebo group, suggesting that poor absorption of the drug formulation and/or poor compliance might have contributed to the decreased cyclosporin blood levels in the patient withdrawn from this study and in previous uncontrolled studies.


CONCLUSIONS
Cyclosporin bioavailability was not clearly modified by a half dosage of ticlopidine in this study. We, however, recommend closely monitoring cyclosporin blood levels when prescribing ticlopidine. Further studies will be needed with new formulations of cyclosporin or when using the full dosage of ticlopidine.
Boissonnat
P
P
Laboratoire de Physiologie, CHU Nord, Saint-Etienne, France.
de Lorgeril
M
M
Perroux
V
V
Salen
P
P
Batt
A M
AM
Barthelemy
J C
JC
Brouard
R
R
Serres
E
E
Delaye
J
J
D000293:Adolescent; D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D016572:Cyclosporine / Q000097:blood / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004311:Double-Blind Method; D004347:Drug Interactions; D016027:Heart Transplantation / Q000502:physiology; D006801:Humans; D006854:Hydrocortisone / Q000031:analogs & derivatives / Q000652:urine; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D010975:Platelet Aggregation Inhibitors / Q000097:blood / Q000494:pharmacology*; D011446:Prospective Studies; D013988:Ticlopidine / Q000097:blood / Q000494:pharmacology*
D007166:Immunosuppressive Agents; D010975:Platelet Aggregation Inhibitors; C001380:6 beta-hydroxycortisol; D016572:Cyclosporine; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D013988:Ticlopidine; D006854:Hydrocortisone