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
- Authors
- Vo, Dang-Khoa; Nguyen, Thi-Thao-Linh; Maeng, Han-Joo
- Issue Date
- May-2024
- Publisher
- SPRINGERNATURE
- Keywords
- 1 alpha,25-dihydroxyvitamin D-3; OCTN2; OCT2; Endogenous biomarkers; Pharmacokinetics; Drug-drug interactions
- Citation
- JOURNAL OF PHARMACEUTICAL INVESTIGATION, v.54, no.3, pp 389 - 402
- Pages
- 14
- Journal Title
- JOURNAL OF PHARMACEUTICAL INVESTIGATION
- Volume
- 54
- Number
- 3
- Start Page
- 389
- End Page
- 402
- URI
- https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/91066
- DOI
- 10.1007/s40005-023-00659-2
- ISSN
- 2093-5552
2093-6214
- Abstract
- Purpose This study investigated effects of 1 alpha,25-dihydroxyvitamin D3 [1,25(OH)(2)D-3] 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)(2)D3 (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)(2)D-3-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)(2)D-3. 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)(2)D-3 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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