Effects of 1α,25-Dihydroxyvitamin D 3 , the Natural Vitamin D Receptor Ligand, on the Pharmacokinetics of Cefdinir and Cefadroxil, Organic Anion Transporter Substrates, in Rat

Kim, Yu Chul; Kim, In-Bong; Noh, Chi-Kyoung; Quach, Holly P.; Yoon, In‐Soo; Chow, Edwin; Kim, Myung-Soo; Jin, Hosub; Cho, Kwan Hyung; Chung, Suk‐Jae; Pang, K. Sandy; Maeng, Han‐Joo

doi:10.1002/jps.24195

Cited by 23 publications

(43 citation statements)

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“…As a result, there were no differences (p>0.05) in total plasma protein, plasma albumin, blood urea nitrogen, sGOT, sGPT and CL cr , indicating that liver and kidney function are normal in 1,25(OH) 2 D 3 -treated rats, compared to control rats (data not shown). However, it is interesting to note that body weight gain was significantly (p<0.05) smaller in 1,25(OH) 2 D 3 -treated rats than in control rats, which was also consistent with our previous reports by Kim et al 29) Effects of 1,25(OH) 2 D 3 on the pharmacokinetics of intravenous adefovir itself in rats were first evaluated. Plasma concentration-time profiles of adefovir after its intravenous administration at a dose of 15 µmol/kg in control and 1,25(OH) 2 D 3 -treated rats are shown in Fig.…”

Section: In Vivo Intravenous Pharmacokinetic Study In Ratssupporting

confidence: 90%

“…From a point of view of clinical relevance, osteomalacia, which is manifested as bone pain and may contribute to fractures, is regarded as an important side-effect of adefovir therapy. [31][32][33] 29) In conclusion, the present study indicates that 1,25(OH) 2 D 3 treatment can enhance the oral absorption of adefovir dipivoxil (i.e., increased AUC of adefovir, a Mrp4 substrate) via the induction of basolateral Mrp4 function in rat intestine. However, the impact of 1,25(OH) 2 D 3 treatment on the pharmacokinetics of intravenous adefovir is quite limited.…”

Section: Discussionmentioning

confidence: 83%

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Effects of 1α,25-Dihydroxyvitamin D<sub>3</sub> on Intestinal Absorption and Disposition of Adefovir Dipivoxil and Its Metabolite, Adefovir, in Rats

Yoon

Son

Kim

et al. 2015

Biological & Pharmaceutical Bulletin

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The aim of this study was to investigate the effect of 1α,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ), an active form of vitamin D, on the oral absorption and disposition of adefovir dipivoxil (P-glycoprotein (P-gp) substrate) and its major active metabolite, adefovir (multidrug resistance-associated protein 4 (Mrp4) substrate), in rats. The pharmacokinetics of intravenous adefovir and oral adefovir dipivoxil was evaluated in control and 1,25(OH) 2 D 3 -treated rats. The intestinal absorption of adefovir dipivoxil was investigated through an in situ closed loop study, and the tissue distribution of adefovir after oral administration of adefovir dipivoxil was evaluated in the two groups. There was no significant difference in pharmacokinetic parameters of intravenous adefovir between the two groups. Importantly, the total area under the plasma concentration-time curve from time zero to time infinity (AUC), peak plasma concentration (C max ) and extent of absolute oral bioavailability (F) of adefovir after oral administration of adefovir dipivoxil were significantly higher in 1,25(OH) 2 D 3 -treated rats than in control rats. In the in situ closed loop study, there was no significant difference in the remaining fraction of adefovir dipivoxil in the duodenum, jejunum and ileum loops between the two groups. In the tissue distribution study after oral administration of adefovir dipivoxil, the tissue-toplasma partition coefficients of adefovir in the liver, brain, kidney, and intestine were significantly lower in 4) During the past decades, significant physiological roles of VDR in calcium and bone homeostasis have been well established. 5)However, it is increasingly recognized that VDR is also crucial in the regulation of drug transporters, and 1,25(OH) 2 D 3 can lead to VDR-mediated changes in target genes of drug transporters. [6][7][8][9][10] Since VDR is abundantly expressed in the intestine, 11) the effects of 1,25(OH) 2 D 3 (i.e., VDR activation) on the expression of intestinal drug transporters are frequently investigated. 1,25(OH) 2 D 3 increases the mRNA expression and function of multidrug resistance protein 1 (MDR1) in the human colorectal adenocarcinoma cell lines, LS174T and Caco-2 cells in vitro. 8,12) It also increases the protein expressions of multidrug resistance-associated protein 2 and 4 (MRP2 and MRP4) in Caco-2 cells. 8,13) In rats, 1,25(OH) 2 D 3 treatment in vivo increases the protein expressions of Mrp2, Mrp3, Mrp4, and the oligopeptide transporter 1 (PepT1) without altering the mRNA and protein expressions of Mdr1a (P-glycoprotein; P-gp). 14)Moreover, our previous studies using rat everted intestinal sac technique confirmed that the in vitro functions of rat intestinal Mrp2, Mrp4 and PepT1, but not P-gp are induced by 1,25(OH) 2 D 3 treatment via VDR activation. 15) However, changes in the expression and/or in vitro functions of drug transporters do not always correlate with the fates of therapeutic agents in the whole body system. Therefore, further studies are needed on the effects of 1,25(O...

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Section: In Vivo Intravenous Pharmacokinetic Study In Ratssupporting

confidence: 90%

Section: Discussionmentioning

confidence: 83%

Effects of 1α,25-Dihydroxyvitamin D<sub>3</sub> on Intestinal Absorption and Disposition of Adefovir Dipivoxil and Its Metabolite, Adefovir, in Rats

Yoon

Son

Kim

et al. 2015

Biological & Pharmaceutical Bulletin

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“…The related drug transporters would be influenced when apoptosis of renal tubular epithelial cells occurred. According to the reports, majority of cephalosporin antibiotics such as cefditoren and cefdinir, the disposition of them was mainly mediated by transporters in kidney (for cefdinir) and in liver (for cefditoren). Previous study had confirmed that cefditoren was the substrate of H+/peptide symporters PEPT1 .…”

Section: Discussionmentioning

confidence: 99%

“…And the hepatic uptake and biliary excretion of cefditoren were mediated by organic anion‐transporting polypeptide 1B1 (OATP1B1) and OATP2B1 in human, and Oatp1a1, Oatp1a4, Oatp1b2 and multidrug resistance‐associated protein 2 (Mrp2) in rats . As for cefdinir, it was a poor substrate of PEPT1 and PEPT2, it just only reported that cefdinir was a substrate of organic anion transporter 1 (OAT1) and OAT3 in kidney . Besides, minimal information about the pharmacokinetics of cefdinir in rats had been reported .…”

Section: Introductionmentioning

confidence: 99%

“…As for cefdinir, it was a poor substrate of PEPT1 and PEPT2, it just only reported that cefdinir was a substrate of organic anion transporter 1 (OAT1) and OAT3 in kidney . Besides, minimal information about the pharmacokinetics of cefdinir in rats had been reported . In addition, the expression and function of renal transporters would be changed under the condition of AKI.…”

Section: Introductionmentioning

confidence: 99%

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Pharmacokinetic changes of cefdinir and cefditoren and its molecular mechanisms in acute kidney injury in rats

Wang

Sun

Wang

et al. 2018

Journal of Pharmacy and Pharmacology

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The molecular mechanism of decreased expression of Oat1 and Oat3 was achieved through activating p53, and then increasing the expression of Bax and Caspase-3 and down regulating Bcl-2 in AKI rats. On this basis, the cumulative urinary excretion of cefdinir was significantly decreased and the plasma concentration of cefdinir was remarkably increased in AKI rats. However, the pharmacokinetic changes of cefditoren were not observed. Accordingly, cephalosporin antibiotics such as cefditoren should be firstly selected for the treatment in patients with AKI in clinic.

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Alterations in gene expression in vitamin D‐deficiency: Down‐regulation of liver Cyp7a1 and renal Oat3 in mice

Quach

Noh

Hoi

et al. 2018

Biopharm & Drug Disp

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The vitamin D-deficient model, established in the C57BL/6 mouse after 8 weeks of feeding vitamin D-deficient diets in the absence or presence of added calcium, was found associated with elevated levels of plasma parathyroid hormone (PTH) and plasma and liver cholesterol, and a reduction in cholesterol 7α-hydroxylase (Cyp7a1, rate-limiting enzyme for cholesterol metabolism) and renal Oat3 mRNA/protein expression levels. However, there was no change in plasma calcium and phosphate levels. Appraisal of the liver revealed an up-regulation of mRNA expressions of the small heterodimer partner (Shp) and attenuation of Cyp7a1, which contributed to hypercholesterolemia in vitamin D-deficiency. When vitamin D-sufficient or D-deficient mice were further rendered hypercholesterolemic with 3 weeks of feeding the respective, high fat/high cholesterol (HF/HC) diets, treatment with 1α,25-dihydroxyvitamin D [1,25(OH) D ], active vitamin D receptor (VDR) ligand, or vitamin D (cholecalciferol) to HF/HC vitamin D-deficient mice lowered the cholesterol back to baseline levels. Cholecalciferol treatment partially restored renal Oat3 mRNA/protein expression back to that of vitamin D-sufficient mice. When the protein expression of protein kinase C (PKC), a known, negative regulator of Oat3, was examined in murine kidney, no difference in PKC expression was observed for any of the diets with/without 1,25(OH) D /cholecalciferol treatment, inferring that VDR regulation of renal Oat3 did not involve PKC in mice. As expected, plasma calcium levels were not elevated by cholecalciferol treatment of vitamin D-deficient mice, while 1,25(OH) D treatment led to hypercalcemia. In conclusion, vitamin D-deficiency resulted in down-regulation of liver Cyp7a1 and renal Oat3, conditions that are alleviated upon replenishment of cholecalciferol.

show abstract

Effects of 1α,25-Dihydroxyvitamin D 3 , the Natural Vitamin D Receptor Ligand, on the Pharmacokinetics of Cefdinir and Cefadroxil, Organic Anion Transporter Substrates, in Rat

Cited by 23 publications

References 50 publications

Effects of 1α,25-Dihydroxyvitamin D<sub>3</sub> on Intestinal Absorption and Disposition of Adefovir Dipivoxil and Its Metabolite, Adefovir, in Rats

Effects of 1α,25-Dihydroxyvitamin D<sub>3</sub> on Intestinal Absorption and Disposition of Adefovir Dipivoxil and Its Metabolite, Adefovir, in Rats

Pharmacokinetic changes of cefdinir and cefditoren and its molecular mechanisms in acute kidney injury in rats

Alterations in gene expression in vitamin D‐deficiency: Down‐regulation of liver Cyp7a1 and renal Oat3 in mice

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