Search

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)2D3with 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.

Purpose: This study aimed to investigate the effects of 1α,25-dihydroxyvitamin D3(1,25(OH)2D3) on the expression levels of organic cation/carnitine transporter 1 (OCTN1) as well as the pharmacokinetics and biodistribution of ergothioneine, an OCTN1 substrate, in rats. Methods: Rats pretreated with 1,25(OH)2D3(2.56 nmol/kg/day) for four days were administered ergothioneine (2 mg/kg) intravenously. The expression levels of rat OCTN1 (rOCTN1) in organs were determined using real-time quantitative polymerase chain reaction. Ergothioneine levels in plasma, urine, and organs (with and without intravenous injection of exogenous ergothioneine) were determined using liquid chromatography-tandem mass spectrometry. Results: 1,25(OH)2D3pretreatment resulted in a significant decrease in rOCTN1 mRNA expression levels in the kidney and brain, a significant increase in basal plasma levels of ergothioneine (from 48 h), and a significant decrease in the tissue-plasma partition coefficient (Kp) in all tissues (except the heart and lungs) and the basal urine levels of ergothioneine. After intravenous administration, the pharmacokinetic profiles of ergothioneine were consistent with the basal levels of endogenous ergothioneine, with an increase in AUC∞by 85%, a significant decrease in total clearance by 49%, and a decrease in Vssby 32% in 1,25(OH)2D3-treated rats. The Kpvalue and urinary recovery of ergothioneine also decreased in the 1,25(OH)2D3-treated group. Conclusion: This study showed the effects of 1,25(OH)2D3on the expression and function of rOCTN1 by investigating the interaction between 1,25(OH)2D3and ergothioneine. Dose adjustment and possible changes in bioavailability should be considered before the co-administration of vitamin D or its active forms and OCTN1 substrates.