Inhibitory effect of JBP485 on renal excretion of acyclovir by the inhibition of OAT1 and OAT3.
The purpose is to investigate whether the targets of drug-drug interactions (DDIs) between JBP485 and acyclovir are OAT1 and OAT3 in kidney. Plasma concentration and accumulative urinary excretion of acyclovir in vivo, uptake of acyclovir in kidney slices and uptake of acyclovir in human (h) OAT1/ hOAT3-human embryonic kidney (HEK) 293 cells in vitro were performed to examine the effect of JBP485 on urinary excretion of acyclovir. The plasma concentration of acyclovir was increased markedly and accumulative urinary excretion and renal clearance of acyclovir were decreased significantly after intravenous administration of acyclovir in combination with JBP485. JBP485 (a substrate for OAT1 and OAT3), p-aminohippurate (PAH) (a substrate for OAT1) and benzylpenicillin (PCG) (a substrate for OAT3) could decrease the uptake of acyclovir in kidney slices and in hOAT1-/hOAT3-HEK293 cells. These results suggest that JBP485 inhibits the renal excretion of acyclovir by inhibiting renal transporters OAT1 and OAT3 in vivo and in vitro. Our results indicate the possibility of DDI between dipeptide and acyclovir.
Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, China.
Jianghao
J
Ye
Qi
Q
Liu
Changyuan
C
Wang
Qiang
Q
Meng
Jinyong
J
Peng
Huijun
H
Sun
Taiichi
T
Kaku
Kexin
K
Liu
D000212:Acyclovir / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004347:Drug Interactions; D057809:HEK293 Cells; D006801:Humans; D066298:In Vitro Techniques; D007668:Kidney / Q000378:metabolism; D008297:Male; D027362:Organic Anion Transport Protein 1 / Q000378:metabolism*; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism*; D010456:Peptides, Cyclic / Q000008:administration & dosage* / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar
D000998:Antiviral Agents; C412308:JBP 485; D027362:Organic Anion Transport Protein 1; D029362:Organic Anion Transporters, Sodium-Independent; D010456:Peptides, Cyclic; C114338:organic anion transport protein 3; D000212:Acyclovir