Pharmacokinetic interactions between microemulsion formulated cyclosporine A and diltiazem in renal transplant recipients.
OBJECTIVE
Bilateral cyclosporin A (CsA) and diltiazem pharmacokinetic interactions have previously been investigated, however, not with the new microemulsion preconcentrate formulation of CsA (Sandimmun Neoral). In addition, the pharmacokinetic effects on the pharmacological active metabolites of diltiazem have not previously been investigated. We performed a pharmacokinetic interaction study in renal transplant recipients, measuring both unmetabolised CsA and diltiazem in addition to three of the main metabolites of diltiazem (MA, M1, M2).


METHODS
Nine CsA-treated renal transplant patients were treated with diltiazem, 90-120 mg b.i.d., for 4 weeks. Pharmacokinetic investigations were performed both before and at the end of the diltiazem treatment period. Six non-CsA-treated renal transplant patients served as controls of CsA interactions with diltiazem and its metabolites.


RESULTS
Diltiazem treatment resulted in a significant mean increase in the area under the concentration time curve (AUC) for CsA of 51(8)% (P < 0.008) and a peak concentration (Cmax) of 34(8)% (P < 0.05), without altering time to peak concentration (tmax). CsA, however, did not significantly influence diltiazem pharmacokinetics, though two of the metabolites (M1 and M2) tended to be increased.


CONCLUSIONS
Diltiazem interacts significantly with the pharmacokinetics of CsA in the new microemulsion formulation. Microemulsion-formulated CsA, however, did not show significant interaction with diltiazem pharmacokinetics.
Asberg
A
A
Department of Pharmacology, School of Pharmacy, University of Oslo, Norway. anderas@farmasi.uio.no
Christensen
H
H
Hartmann
A
A
Carlson
E
E
Molden
E
E
Berg
K J
KJ
D000328:Adult; D000368:Aged; D000959:Antihypertensive Agents / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D016572:Cyclosporine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D004110:Diltiazem / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D004347:Drug Interactions; D004655:Emulsions; D004791:Enzyme Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D016030:Kidney Transplantation / Q000502:physiology*; D008297:Male; D008875:Middle Aged
D000959:Antihypertensive Agents; D004655:Emulsions; D004791:Enzyme Inhibitors; D016572:Cyclosporine; D004110:Diltiazem