The concentration of cyclosporine metabolites is significantly lower in kidney transplant recipients with diabetes mellitus.
BACKGROUND
Diabetes mellitus is prevalent among kidney transplant recipients. The activity of drug metabolizing enzymes or transporters may be altered by diabetes leading to changes in the concentration of parent drug or metabolites. This study was aimed to characterize the effect of diabetes on the concentration of cyclosporine (CsA) and metabolites.


METHODS
Concentration-time profiles of CsA and metabolites (AM1, AM9, AM4N, AM1c, AM19, and AM1c9) were characterized over a 12-hour dosing interval in 10 nondiabetic and 7 diabetic stable kidney transplant recipients. All patients were male, had nonfunctional CYP3A5*3 genotype, and were on combination therapy with ketoconazole.


RESULTS
The average daily dose (±SD) of CsA was 65 ± 21 and 68 ± 35 mg in nondiabetic and diabetic subjects, respectively (P = 0.550). Cyclosporine metabolites that involved amino acid 1 (AM1, AM19, AM1c) exhibited significantly lower dose-normalized values of area under the concentration-time curve in patients with diabetes. Moreover, during the postabsorption phase (≥3 hours after dose), metabolite-parent concentration ratios for all metabolites, except AM4N, was significantly lower in diabetic patients. The pharmacokinetic parameters of ketoconazole were similar between the 2 groups thus excluding inconsistent ketoconazole exposure as a source of altered CsA metabolism.


CONCLUSIONS
This study indicates that diabetes mellitus significantly affects the concentration of CsA metabolites. Because CsA is eliminated as metabolites via the biliary route, the decrease in the blood concentration of CsA metabolites during postabsorption phase would probably reflect lower hepatic cytochrome P450 3A4 enzyme activity. However, other mechanisms including altered expression of transporters may also play a role. Results of cyclosporine therapeutic drug monitoring in diabetic patients must be interpreted with caution when nonspecific assays are used.
Department of Biomedical and Pharmaceutical Sciences, Clinical Pharmacokinetics Research Laboratory, University of Rhode Island, Kingston, Rhode Island 02881, USA. fatemeh@uri.edu
Fatemeh
F
Akhlaghi
Miroslav
M
Dostalek
Pål
P
Falck
Anisha E
AE
Mendonza
Rune
R
Amundsen
Reginald Y
RY
Gohh
Anders
A
Asberg
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000368:Aged; D016572:Cyclosporine / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D003920:Diabetes Mellitus / Q000378:metabolism*; D005786:Gene Expression Regulation; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007166:Immunosuppressive Agents; D016572:Cyclosporine; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A