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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

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Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusion

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.

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Acknowledgements

This work was supported by the Gachon University Research Fund of 2020 (GCU- 202008420005) and the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (NRF-2021R1F1A1060378).

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  1. College of Pharmacy, Gachon University, 191 Hambakmoe-ro, Yeonsu-gu, Incheon, 21936, Korea

    Dang-Khoa Vo, Thi-Thao-Linh Nguyen & Han-Joo Maeng

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Vo, DK., Nguyen, TTL. & Maeng, HJ. 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. J. Pharm. Investig. 54, 389–402 (2024). https://doi.org/10.1007/s40005-023-00659-2

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