title: Effects of 1α,25-dihydroxyvitamin D3 , the natural vitamin D receptor ligand, on the pharmacokinetics of cefdinir and cefadroxil, organic anion transporter substrates, in rat.
abstract: Evidence in the literature suggests that 1α,25-dihydroxyvitamin D3 [1,25(OH)2 D3 ], the vitamin D receptor ligand, down-regulated the expression of the rat renal organic anion (renal organic anion transporter, rOAT) and oligopeptide (rPEPT) transporters, but increased intestinal rPEPT1 expression. We investigated, in rats, the intravenous and oral pharmacokinetics of 2 mg/kg cefdinir and cefadroxil, two cephalosporins that are eliminated via renal OAT1/OAT3 and are substrates of PEPT1/PEPT2, with and without 1,25(OH)2 D3 treatment. The area under the plasma concentration-time curve (AUC) of cefdinir or cefadroxil after 1,25(OH)2 D3 treatment was increased significantly because of decreased clearance (CL). Both kidney uptake and cumulative urinary recovery were significantly decreased, whereas liver uptake and fecal recovery remained unchanged in 1,25(OH)2 D3 -treated rats. Similar changes in AUC and CL were observed for both drugs upon coadministration of probenecid, the OAT inhibitor. Oral availability of cefdinir and cefadroxil remained unchanged with 1,25(OH)2 D3 treatment, suggesting lack of a role for intestinal rPEPT1. Rather, reduction of rOAT1/rOAT3 mRNA expression in kidney with 1,25(OH)2 D3 -treatment was observed, confirmed by decreased function in MDCKII cells overexpressing human OAT1 and OAT3. These composite results suggest that 1,25(OH)2 D3 treatment reduces cefdinir and cefadroxil clearances by diminution of renal OAT1/OAT3 expression, implicating a role for 1,25(OH)2 D3 in eliciting transporter-based drug interactions.
authors.affiliation: C&C Research Laboratories, Suwon, Gyeonggi, Republic of Korea.
authors.forename: Yu Chul
authors.initials: YC
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Inje University, Gimhae, Gyeongnam 621-749, Republic of Korea.
authors.forename: In-Bong
authors.initials: IB
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Seoul National University, Seoul, Republic of Korea.
authors.forename: Chi-Kyoung
authors.initials: CK
authors.lastname: Noh
authors.affiliation: Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Holly P
authors.initials: HP
authors.lastname: Quach
authors.affiliation: College of Pharmacy, and Natural Medicine Research Institute, Mokpo National University, Jeonnam 534-729, Republic of Korea.
authors.forename: In-Soo
authors.initials: IS
authors.lastname: Yoon
authors.affiliation: Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Edwin C Y
authors.initials: ECY
authors.lastname: Chow
authors.affiliation: College of Pharmacy, Inje University, Gimhae, Gyeongnam 621-749, Republic of Korea.
authors.forename: Myungsoo
authors.initials: M
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Seoul National University, Seoul, Republic of Korea.
authors.forename: Hyo-Eon
authors.initials: HE
authors.lastname: Jin
authors.affiliation: College of Pharmacy, Inje University, Gimhae, Gyeongnam 621-749, Republic of Korea.
authors.forename: Kwan Hyung
authors.initials: KH
authors.lastname: Cho
authors.affiliation: College of Pharmacy, Seoul National University, Seoul, Republic of Korea.
authors.forename: Suk-Jae
authors.initials: SJ
authors.lastname: Chung
authors.affiliation: Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
authors.forename: K Sandy
authors.initials: KS
authors.lastname: Pang
authors.affiliation: College of Pharmacy, Inje University, Gimhae, Gyeongnam 621-749, Republic of Korea. Electronic address: maenghj@inje.ac.kr.
authors.forename: Han-Joo
authors.initials: HJ
authors.lastname: Maeng
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D002117:Calcitriol / Q000008:administration & dosage*; D002434:Cefadroxil / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000652:urine; D000077525:Cefdinir; D002511:Cephalosporins / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000652:urine; D004285:Dogs; D015536:Down-Regulation; D004347:Drug Interactions; D006801:Humans; D007275:Injections, Intravenous; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008024:Ligands; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D027362:Organic Anion Transport Protein 1 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D000074011:Peptide Transporter 1; D012333:RNA, Messenger / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D018167:Receptors, Calcitriol / Q000819:agonists*; D065667:Renal Elimination / Q000187:drug effects; D027981:Symporters / Q000378:metabolism; D014018:Tissue Distribution; D014162:Transfection
chemical_list: D002511:Cephalosporins; D008024:Ligands; D027362:Organic Anion Transport Protein 1; D029362:Organic Anion Transporters, Sodium-Independent; D000074011:Peptide Transporter 1; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; C489940:Slc15a1 protein, rat; C421043:Slc22a6 protein, rat; D027981:Symporters; C093694:hydrogen-coupled oligopeptide transporter PepT2; C114338:organic anion transport protein 3; D002434:Cefadroxil; D000077525:Cefdinir; D002117:Calcitriol
keywords: 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3]; cefadroxil; cefdinir; clearance; drug interactions; elimination; organic anion transporter 1 (OAT1) and 3 (OAT3); pharmacokinetics; renal excretion