Effects of 1α,25-dihydroxyvitamin D3 on the pharmacokinetics and biodistribution of ergothioneine, an endogenous organic cation/carnitine transporter 1 substrate, in rats

Dang-Khoa Vo; Thi-Thao-Linh Nguyen; Han-Joo Maeng

doi:10.1007/s40005-022-00563-1

Effects of 1α,25-dihydroxyvitamin D₃ on the pharmacokinetics and biodistribution of ergothioneine, an endogenous organic cation/carnitine transporter 1 substrate, in rats

J Pharm Investig. 2022;52(3):341-351. doi: 10.1007/s40005-022-00563-1. Epub 2022 Mar 10.

Authors

Dang-Khoa Vo¹, Thi-Thao-Linh Nguyen¹, Han-Joo Maeng¹

Affiliation

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

Abstract

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)₂D₃ 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_∞ by 85%, a significant decrease in total clearance by 49%, and a decrease in V_ss by 32% in 1,25(OH)₂D₃-treated rats. The K_p value 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)₂D₃ on the expression and function of rOCTN1 by investigating the interaction between 1,25(OH)₂D₃ 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.

Supplementary information: The online version contains supplementary material available at 10.1007/s40005-022-00563-1.

Keywords: 1α,25-Dihydroxyvitamin D3; Biodistribution; Ergothioneine; OCTN1 substrate; Pharmacokinetics.