Effects of 1α,25-Dihydroxyvitamin D3 on the Pharmacokinetics of Procainamide and Its Metabolite N-Acetylprocainamide, Organic Cation Transporter Substrates, in Rats with PBPK Modeling Approach.

Anusha Balla,Suk-Jae Chung,Yun-Jong Lee,Yoon-Jee Chae,Han-Joo Maeng,Yoo-Seong Jeong,Hyo-Jung Kim

doi:10.3390/pharmaceutics13081133

Anusha Balla, Suk-Jae Chung + Show 5 more

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https://doi.org/10.3390/pharmaceutics13081133

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Abstract

In this study, possible changes in the expression of rat organic cationic transporters (rOCTs) and rat multidrug and toxin extrusion proteins (rMATEs) following treatment with 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) were investigated. Rats received intraperitoneal administrations of 1,25(OH)2D3 for four consecutive days, and the tissues of interest were collected. The mRNA expression of rOCT1 in the kidneys was significantly increased in 1,25(OH)2D3-treated rats compared with the control rats, while the mRNA expressions of rOCT2 and rMATE1 in the kidneys, rOCT1 and N-acetyltransferase-II (NAT-II) in the liver, and rOCT3 in the heart were significantly decreased. Changes in the protein expression of hepatic rOCT1 and renal rOCT2 and rMATE1 were confirmed by western blot analysis. We further evaluated the pharmacokinetics of procainamide (PA) hydrochloride and its major metabolite N-acetyl procainamide (NAPA) in the presence of 1,25(OH)2D3. When PA hydrochloride was administered intravenously at a dose 10 mg/kg to 1,25(OH)2D3-treated rats, a significant decrease in renal and/or non-renal clearance of PA and NAPA was observed. A physiological model for the pharmacokinetics of PA and NAPA in rats was useful for linking changes in the transcriptional and translational expressions of rOCTs and rMATE1 transporters to the altered pharmacokinetics of the drugs.

Highlights

Drug transporters are crucial factors that affect the pharmacokinetics of therapeutic drugs
Despite the relatively lower expression of rOCT1 compared to rOCT2 in rat kidneys (38.3 compared to 254 pmol/g kidney) [38], PSin may be involved with the active (PSact) was assumed to be composed of PSrOCT1 and PSrOCT2 since this study revealed a significant increase in rOCT1 expression along with a significant decrease in rOCT2 by 1,25(OH)2 D3 treatment
The mRNA/protein expression of rOCT1 was significantly increased in the kidneys of 1,25(OH)2 D3 -treated rats compared with control rats, whereas the mRNA or protein levels of rOCT2 and rMATE1 in the kidney, rOCT1 and rNAT-II in the liver, and rOCT3 in the heart were significantly decreased

Summary

Introduction

Drug transporters are crucial factors that affect the pharmacokinetics of therapeutic drugs. Changes in the expression and/or function of such biological proteins may alter drug disposition, toxicology, and pharmacological responses at the site of action. Previous studies [1,2] have reported changes in the expression of adenosine triphosphate (ATP)binding cassette or solute carrier membrane transporters in various tissues, including in the kidney, liver, and brain, under pathological conditions. The administration of some therapeutic drugs has been reported to alter the expression levels of transporters [3,4]. The gene expression of transporters and drug-metabolizing enzymes, which may affect the pharmacokinetic profiles of drugs, is known to be regulated by nuclear receptor proteins including pregnane X receptor (PXR), constitutive androstane receptor (CAR), farnesoid X receptor (FXR), and vitamin D receptor (VDR) [5,6].

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