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Pharmacokinetics of the cyclosporine-ketoconazole interaction in dogs

D'mello, A and Venkataramanan, R and Satake, M and Todo, S and Takaya, S and Ptachcinski, RJ and Burckart, GJ and Starzl, TE (1989) Pharmacokinetics of the cyclosporine-ketoconazole interaction in dogs. Research Communications in Chemical Pathology and Pharmacology, 64 (3). 441 - 454. ISSN 0034-5164

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Abstract

Numerous clinical reports have documented an increase in trough blood concentrations of cyclosporine in transplant recipients treated concomitantly with ketoconazole. The objective of this study was to elucidate the mechanism(s) underlying the cyclosporine-ketoconazole interaction using a choledochoureterostomy dog model. Five male beagle dogs received a 4 mg/kg, i.v. bolus dose of cyclosporine either alone or on day seven of a 10-day, 13 mg/kg/day, oral dosing regimen of ketoconazole. Blood samples were collected prior to and at predetermined times for 60 hrs after the cyclosporine dose, while the bile/urine mixture was collected quantitatively for 96 hours after the cyclosporine dose. Ketoconazole decreased the systemic clearance of cyclosporine from 7.0 ml/min/kg to 2.5 ml/min/kg. The terminal disposition rate constant was also decreased significantly from 0.0794 to 0.0354 hrs-1. Ketoconazole caused no significant changes in cyclosporine steady state volume of distribution, or plasma unbound fraction. Ketoconazole did not significantly alter the excretion of cyclosporine and various cyclosporine metabolites in the bile/urine mixture. Inhibition of hepatic drug metabolizing enzymes appears to be the primary reason for the ketoconazole induced elevation in cyclosporine concentration.

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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
D'mello, A
Venkataramanan, Rrv@pitt.eduRV
Satake, M
Todo, S
Takaya, S
Ptachcinski, RJ
Burckart, GJ
Starzl, TEtes11@pitt.eduTES11
Centers: Other Centers, Institutes, Offices, or Units > Thomas E. Starzl Transplantation Institute
Date: 1 January 1989
Date Type: Publication
Journal or Publication Title: Research Communications in Chemical Pathology and Pharmacology
Volume: 64
Number: 3
Page Range: 441 - 454
Institution: University of Pittsburgh
Refereed: Yes
ISSN: 0034-5164
Other ID: uls-drl:31735062110691, Starzl CV No. 1027
Date Deposited: 08 Apr 2010 17:17
Last Modified: 22 Jun 2021 10:55
URI: http://d-scholarship.pitt.edu/id/eprint/4413

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