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

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.

Synthetic Peucedanocoumarin IV Prevents α-Synuclein Neurotoxicity in an Animal Model of Parkinson’s Disease

“…In vivo rat pharmacokinetic studies were performed for intravenous and oral administration of PCiv as previously reported [ 16 , 17 , 18 ]. Sprague-Dawley rats (8 weeks old, 260–280 g) were purchased from Orient Bio Inc. (Seongnam, Korea).…”

“…The plasma fraction was immediately obtained after centrifugation at 14,000 rpm for 15 min at 4 °C and then stored at −20 °C prior to analysis using the ultra-high-performance liquid chromatography (UHPLC)-diode array detector (DAD) method. Similarly, a tissue distribution study was performed 15 min after the intravenous bolus injection (10 mg/kg), as previously described [ 17 , 18 ]. Four major tissues, including tissues from the brain, heart, kidneys, and liver, were collected.…”

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

“…Our recent study also demonstrated that 1,25(OH) 2 D 3 downregulates the mRNA and protein expression of Cyp2b1 and Cyp2c11 in rats, which consequently alters the metabolic function and systemic pharmacokinetics of bupropion and tolbutamide (substrates of Cyp2b1 and Cyp2c11, respectively) (Doan et al 2020). In another recent study of our group, 1,25(OH) 2 D 3 regulated the expression of rat organic cation transporters (rOCT) and rat multidrug and toxin extrusion proteins (rMATE), which was evidenced by a decrease in renal and non-renal (metabolic) clearance of procainamide hydrochloride (an organic cation transporter substrate) and a decrease in the renal clearance of the metabolite N-acetyl procainamide (Balla et al 2021). Organic cation/carnitine transporter 1 (OCTN1), also called the ergothioneine transporter (Gründemann et al 2005), is a member of the SLC22 family, which is strongly expressed in the rat liver (Koepsell and Endou 2004;Pangeni et al 2021).…”

“…Male Sprague Dawley rats (7-8 weeks old, 220-280 g; Nara Bio Tech., South Korea) were acclimated to laboratory conditions and provided ad libitum access to food and water and maintained under 12-h/12-h light/dark cycles for one week. The treatment of 1,25(OH) 2 D 3 (2.56 nmol/kg/day) was performed as previously reported (Chow et al 2009(Chow et al , 2010Maeng et al 2011;Doan et al 2020;Balla et al 2021). Rats were randomly divided into the control and 1,25(OH) 2 D 3treated groups.…”

“…According to the manufacturer's procedure and a slight modification to optimize the thermal conditions for target genes, the amplification and detection of reaction mixtures were evaluated using the MxPro-Mx3005 software with the following thermal conditions: 95 °C for 10 min, 40 cycles of 95 °C for 15 s, and 56 °C for 30 s, followed by the melting curve. The experiment was carried out using the comparative quantification mode, and the delta-delta method (2 −ΔΔCt ) for relative mRNA quantification was used to calculate the fold expression (Maeng et al 2012;Doan et al 2020;Balla et al 2021). The qPCR primer pairs used were as follows: rGAPDH forward primer 5′-CGC TGG TGC TGA GTA TGT CG-3′; rGAPDH reverse primer 5′-CTG TGG TCA TGA GCC CTT CC-3′; rOCTN1 forward primer 5′-AGC ATT TGT CCT GGG AAC AG-3′; rOCTN1 reverse primer 5′-ACT CAG GGA TGA ACC ACC AG-3′.…”