Effects of 1 alpha,25-dihydroxyvitamin D-3 on the pharmacokinetics and biodistribution of ergothioneine, an endogenous organic cation/carnitine transporter 1 substrate, in rats

Abstract

Purpose This study aimed to investigate the effects of 1 alpha,25-dihydroxyvitamin D-3 (1,25(OH)(2)D-3) 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)(2)D-3 (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)(2)D-3 pretreatment 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 (K-p) 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(infinity) by 85%, a significant decrease in total clearance by 49%, and a decrease in V-ss by 32% in 1,25(OH)(2)D-3-treated rats. The K-p value and urinary recovery of ergothioneine also decreased in the 1,25(OH)(2)D-3-treated group. Conclusion This study showed the effects of 1,25(OH)(2)D-3 on the expression and function of rOCTN1 by investigating the interaction between 1,25(OH)(2)D-3 and 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.