Impact of 1α,25-dihydroxyvitamin D₃ on biodistribution and pharmacokinetics of L-carnitine and creatinine, organic cation/carnitine transporter 2 and organic cation transporter 2 biomarkers

This study investigated effects of 1α,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃] on biodistribution and pharmacokinetics of L-carnitine and creatinine as organic cation/carnitine transporter 2 (OCTN2) and organic cation transporter 2 (OCT2) biomarkers, respectively, together with mRNA expressional changes.

After four consecutive days of pretreatment with 1,25(OH)₂D₃ (2.56 nmol/kg/day), plasma, urine, and tissues were collected for analysis of endogenous L-carnitine and creatinine basal levels, or rats were intravenously administered exogenous L-carnitine (50 mg/kg). The selected tissues were subjected to analysis of rOCTN2 and rOCT2 gene expression using real-time quantitative polymerase chain reaction. The quantification of L-carnitine and creatinine was performed with liquid chromatography-tandem mass spectrometry.

1,25(OH)₂D₃-treated rats exhibited decreased rOCTN2 mRNA expression in the liver, kidney, spleen, and brain, and decreased rOCT2 mRNA expression in the kidney. L-carnitine levels indicated that basal plasma abundance in the 1,25(OH)₂D₃-treated group elevated, whereas the tissue-plasma partition coefficient dropped in all tissues and the urine level also reduced. Exogenous L-carnitine pharmacokinetics were consistent with the endogenous level, with a significant rise in area under the curve and significant decreases in renal clearance and volume of distribution at steady state in the group treated with 1,25(OH)₂D₃. Additionally, the significant increase in plasma levels and decrease in renal clearance of creatinine were likely due to decreased OCT2 function.

Our observations suggest the risk of co-administering 1,25(OH)₂D₃ with OCT2 and/or OCTN2 substrates. Moreover, this study confirmed that L-carnitine and creatinine are sensitive endogenous biomarkers of OCTN2- and OCT2-mediated drug-drug interactions, respectively.