Differential regulation of intestinal and hepatic CYP3A by 1α,25‐dihydroxyvitamin D₃: Effects on in vivo oral absorption and disposition of buspirone in rats

Abstract

1α,25‐Dihydroxyvitamin D3 (also called 1,25(OH)2D3 or calcitriol) is the biologically active form of vitamin D, which functions as a ligand to the vitamin D receptor (VDR). It was previously reported that intestinal cytochrome P450 3A (CYP3A) expression was altered by 1,25(OH)2D3‐mediated VDR activation. However, to clarify whether the change in CYP3A subfamily expression by VDR activation can affect metabolic function, further evidence is needed to prove the effect of 1,25(OH)2D3 treatment on CYP3A‐mediated drug metabolism and pharmacokinetics. Here, we report the effects of 1,25(OH)2D3 on CYP3A activity and in vivo pharmacokinetics of buspirone in Sprague–Dawley rats. CYP3A mRNA expression and CYP3A‐mediated testosterone metabolism were enhanced in the intestine but were unaffected in the livers of rats treated with 1,25(OH)2D3. Notably, the oral pharmacokinetic profile of buspirone (CYP3A substrate drug) and 6′‐hydroxybuspirone (major active metabolite of buspirone formed via CYP3A‐mediated metabolism) was significantly altered, while its intravenous pharmacokinetic profile was not affected by 1,25(OH)2D3 treatment. To the best of our knowledge, this study provides the first reported data regarding the effects of 1,25(OH)2D3 treatment on the in vivo pharmacokinetics of intravenous and oral buspirone in rats, by the differential modulation of hepatic and intestinal CYP3A activity. Our present results could lead to further studies in clinically significant CYP3A‐mediated drug–nutrient interactions with 1,25(OH)2D3, including 1,25(OH)2D3–buspirone interaction. Preclinical Research & Development

Differential Effects of 1α,25-Dihydroxyvitamin D3 on the Expressions and Functions of Hepatic CYP and UGT Enzymes and Its Pharmacokinetic Consequences In Vivo

“…In the Caco-2 cells pretreated with VDR ligand drugs containing 1,25(OH) 2 D 3, it was consistently reported the CYP3A4 protein expression level was significantly induced [9], which had been demonstrated that CYP3A4 expression was upregulated by 1,25(OH) 2 D 3 via binding to the specific vitamin D response element (VDRE) [17]. In a recent study, we found the expression and function of intestinal and hepatic CYP3A were differentially changed by 1,25(OH) 2 D 3 treatment in vivo, and that these changes had significant impacts on the oral absorption and disposition of buspirone (a CYP3A substrate drug) in rats [2]. Likewise, the co-administration of ergocalciferol and cholecalciferol markedly reduced the plasma levels of atorvastatin, a CYP3A4 substrate, and its active metabolites in human [18].…”

“…The dosing solutions were administered intraperitoneally to rats at a dose of 1 mL/kg/day (2.56 nmol/kg/day as 1,25(OH) 2 D 3 ) over four consecutive days. On the fifth day, rats were used for pharmacokinetic study [2,11,12,16,27].…”

“…GAPDH was used as the internal reference gene for normalization. The forward and reverse primers used for qPCR analysis are listed in Supplementary Table S1 [2,25,28,29].…”

“…Vitamin D 3 is synthesized from 7-dehydroxycholesterol in the skin or acquired from diet [1], and is sequentially metabolized through two hydroxylation steps in the liver and kidney to 1α,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 , calcitriol), the active metabolite [2]. Further, 1,25(OH) 2 D 3 regulates calcium and phosphorus homeostasis in mineral-regulating organs, such as the intestine, bone, kidney, and parathyroid glands by binding to vitamin D receptor (VDR) [3], and has been widely used to treat hypocalcemia, metabolic bone diseases, hypoparathyroidism, and cancer [2,4]. In addition, nonclinical studies reported that 1,25(OH) 2 D 3 has several biological effects, which include antitumor [5], T-cell immunomodulatory [6], and neuroprotective effects [7].…”

In Vitro and In Vivo Assessment of Metabolic Drug Interaction Potential of Dutasteride with Ketoconazole

“…The rats were acclimatized in a clean room of the Laboratory Animal Center of Pusan National University (Busan, Korea) for 1 week. Then, they were fasted for 12 h prior to the pharmacokinetic experiment and then anesthetized by intramuscular injection of Zoletil at a dose of 20 mg/kg [20,21]. The femoral vein and artery of the rats were cannulated with a polyethylene tube (BD Medical; Franklin Lakes, NJ, USA).…”