Tacrolimus oral bioavailability doubles with coadministration of ketoconazole.
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.


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.
Floren
L C
LC
Department of Biopharmaceutical Sciences, University of California, San Francisco, USA.
Bekersky
I
I
Benet
L Z
LZ
Mekki
Q
Q
Dressler
D
D
Lee
J W
JW
Roberts
J P
JP
Hebert
M F
MF
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000284:Administration, Oral; D000328:Adult; D000935:Antifungal Agents / Q000494:pharmacology*; D001682:Biological Availability; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D007654:Ketoconazole / Q000494:pharmacology*; D008297:Male; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors; D016559:Tacrolimus / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000935:Antifungal Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D007166:Immunosuppressive Agents; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D007654:Ketoconazole; D016559:Tacrolimus