A drug interaction study between ticlopidine and cyclosporin in heart transplant recipients |
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Authors: | P Boissonnat M de Lorgeril V Perroux P Salen A M Batt J C Barthelemy R Brouard E Serres J Delaye |
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Institution: | Service de Cardiologie B , H?pital Cardiovasculaire, 59 Boulevard Pinel, F-69003 Lyon, France, FR Laboratoire de Physiologie, Explorations fonctionnelles Cardio-Respiratoires, CHU Nord, Niveau 6, F-42055 Saint-Etienne cedex 2, France Tel 33 4 77 82 80 04; Fax 33 4 77 82 84 47, FR CNRS URA 597, Centre du Médicament, Faculté des Sciences Pharmaceutiques, Nancy, France, FR SANOFI Recherche, Montpellier, France, FR
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Abstract: | Objectives: 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-β-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patient in the ticlopidine group was withdrawn because of a major fall in cyclosporin blood level within 3 days of treatment.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-β-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.
Conclusion: 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.
Received: 20 July 1996 / Accepted in revised form: 12 February 1997 |
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Keywords: | Ticlopidine Cyclosporin heart transplanta tion cytochrome P450-3A4 drug interaction |
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