title: Peptide cotransporter 1 in intestine and organic anion transporters in kidney are targets of interaction between JBP485 and lisinopril in rats.
abstract: The purpose of this study was to clarify the pharmacokinetic mechanism of interaction between JBP485 (cyclo-trans-4-L-hydroxyprolyl-L-serine, a dipeptide with antihepatitis activity) and lisinopril (an angiotensin-converting enzyme inhibitor) in vitro and in vivo. When JBP485 and lisinopril were administered orally simultaneously, the plasma concentrations of the two drugs were decreased significantly, but few changes were observed after simultaneous intravenous administration of the two drugs. The uptake of JBP485 and lisinopril in everted intestinal sacs and in HeLa cells transfected with human peptide cotransporter 1 (PEPT1), as well as absorption of JBP485 and lisinopril after jejunal perfusion were reduced after simultaneous drug administration, which suggested that the first target of drug interaction was PEPT1 in the intestine during the absorption process. The cumulative urinary excretions and renal clearance of the two drugs were decreased after intravenous co-administration, while uptakes of the two drugs in kidney slices and hOAT1/hOAT3-transfected HEK293 cells were decreased. These results indicated that the second target of drug-drug interaction was located in the kidney. These findings confirmed that the pharmacokinetic mechanism of interaction between JBP485 and lisinopril could be explained by their inhibition of the same transporters in the intestinal mucosa (PEPT1) and kidneys (OATs).
authors: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China.
authors: Xinjin
authors: X
authors: Guo
authors: Qiang
authors: Q
authors: Meng
authors: Qi
authors: Q
authors: Liu
authors: Changyuan
authors: C
authors: Wang
authors: Qi
authors: Q
authors: Mao
authors: Huijun
authors: H
authors: Sun
authors: Jinyong
authors: J
authors: Peng
authors: Taiichi
authors: T
authors: Kaku
authors: Kexin
authors: K
authors: Liu
mesh_terms: D000818:Animals; D016503:Drug Delivery Systems / Q000379:methods; D004347:Drug Interactions / Q000502:physiology; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D017706:Lisinopril / Q000008:administration & dosage / Q000378:metabolism*; D008297:Male; D027362:Organic Anion Transport Protein 1 / Q000378:metabolism; D027361:Organic Anion Transporters / Q000378:metabolism*; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism; D000074011:Peptide Transporter 1; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D027981:Symporters / Q000378:metabolism*
chemical_list: C412308:JBP 485; D027362:Organic Anion Transport Protein 1; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; D000074011:Peptide Transporter 1; D010456:Peptides, Cyclic; C082186:SLC15A1 protein, human; D027981:Symporters; C114338:organic anion transport protein 3; D017706:Lisinopril