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Tacrolimus oral bioavailability doubles with coadministration of ketoconazole*
- Source :
- Clinical Pharmacology & Therapeutics. 62:41-49
- Publication Year :
- 1997
- Publisher :
- Springer Science and Business Media LLC, 1997.
-
Abstract
- Objective To quantitate the effect of ketoconazole, an azole antifungal agent and potent inhibitor of CYP3A4 and P-glycoprotein, on the bioavailability of tacrolimus, a substrate of the CYP3A system and of P-glycoprotein. Subjects and Methods The pharmacokinetics of tacrolimus were studied in six healthy volunteers (two women and four men) in a four-dose study after each received single doses of tacrolimus alone (0.1 mg/kg orally and 0.025 mg/kg intravenously) and with coadministered ketoconazole (200 mg orally at bedtime for 12 days). The dose of tacrolimus was reduced during the ketoconazole phase (0.04 mg/kg orally; 0.01 mg/kg intravenously). Ketoconazole and tacrolimus doses were separated by approximately 10 hours. Whole blood tacrolimus concentrations were determined by enzyme-linked immunosorbent assay. Estimated pharmacokinetic parameters in whole blood (mean ± SD) before and with ketoconazole were calculated with noncompartmental techniques. Results Coadministration of ketoconazole did not consistently affect tacrolimus clearance (55.6 ± 16.7 ml/hr/kg versus 42.5 ± 7.6 ml/hr/kg), and steady-state volume of distribution was unchanged (0.99 ± 0.26 L/kg versus 0.93 ± 0.25 L/kg). However, a significant increase in tacrolimus bioavailability (14% ± 5% versus 30% ± 8%; p < 0.01) was observed with coadministered ketoconazole. Hepatic bioavailability was unchanged by the presence of ketoconazole (96% ± 1% versus 97% ± 1%). Conclusions Because ketoconazole did not alter hepatic bioavailability and because 10 hours separated administration times of the drugs, it appears that the marked increase in tacrolimus bioavailability can be explained by ketoconazole having a local inhibitory effect on tacrolimus gut metabolism or on intestinal P-glycoprotein activity. Clinical Pharmacology & Therapeutics (1997) 62, 41–49; doi
- Subjects :
- Adult
Male
Antifungal Agents
Administration, Oral
Biological Availability
chemical and pharmacologic phenomena
Pharmacology
Tacrolimus
Mixed Function Oxygenases
Pharmacokinetics
Oral administration
medicine
Cytochrome P-450 CYP3A
Cytochrome P-450 Enzyme Inhibitors
Humans
Pharmacology (medical)
ATP Binding Cassette Transporter, Subfamily B, Member 1
Whole blood
Volume of distribution
Chemistry
Drug interaction
Bioavailability
Ketoconazole
surgical procedures, operative
Female
Immunosuppressive Agents
medicine.drug
Subjects
Details
- ISSN :
- 15326535 and 00099236
- Volume :
- 62
- Database :
- OpenAIRE
- Journal :
- Clinical Pharmacology & Therapeutics
- Accession number :
- edsair.doi.dedup.....01daeec81d778f5dd0000d85fbf103bd