title: Effect of Multi Drug Resistance Protein 4 (MRP4) Inhibition on the Pharmacokinetics and Pharmacodynamics of Ciprofloxacin in Normal and Rats with LPS-Induced Inflammation.
abstract: OBJECTIVE
  Infection and inflammation are known to cause wide variability in disposition of drugs through modulation of drug transporters. However, the effects of inhibition of multidrug resistance protein 4 (MRP4) on pharmacokinetics and pharmacodynamics are poorly understood in normal and inflamed conditions. We hypothesized that inflammation alters the pharmacokinetic parameters of ciprofloxacin; and Pharmacokinetic/Pharmacodynamic indices, such as ratio of peak plasma concentration to minimum inhibitory concentration (Cmax/MIC) and ratio of area under the plasma drug concentration-time curve to minimum inhibitory concentration (AUC/MIC) of ciprofloxacin will be improved with the co-administration of a MRP4 inhibitor, dipyridamole, in inflammatory conditions.
  
  
  METHODS
  In this study, the role of MRP4 on the pharmacokinetic and pharmacodynamic parameters of ciprofloxacin was investigated by the co-administration of dipyridamole in rats with or without lipopolysaccharide (LPS)-induced inflammation. The pharmacokinetic parameters for ciprofloxacin were calculated by non-compartmental approach. MIC of ciprofloxacin was determined using broth microdilution technique.
  
  
  RESULTS
  Induction of inflammation in rats resulted in marked reduction in Cmaxand AUC; and an increase in the volume of distribution (Vd/F) and clearance (Cl/F) of ciprofloxacin, compared to normal rats. Co-administration of dipyridamole with ciprofloxacin in inflamed rats resulted in a threefold increase in AUC, a twofold decrease in Vd/F and a threefold decrease in Cl/F of ciprofloxacin with significantly prolonged half-life compared to inflamed rats who received ciprofloxacin alone. Co-administration of dipyridamole enhanced AUC/MIC values of ciprofloxacin in both normal and inflamed rats.
  
  
  CONCLUSIONS
  The results suggest that MRP4 inhibition increases the systemic exposure of ciprofloxacin in both normal and inflammatory conditions.
authors.affiliation: Department of Veterinary Pharmacology and Toxicology, College of Veterinary Science, Hyderabad, 500 030, India.
authors.forename: V Gangadhara N V
authors.initials: VG
authors.lastname: Prasad
authors.affiliation: Department of Anesthesiology, Duke University Medical Center, Durham, NC, 27701, USA.
authors.forename: Satyanarayana
authors.initials: S
authors.lastname: Achanta
authors.affiliation: Department of Veterinary Parasitology, NTR College of Veterinary Science, Gannavaram, Andhra Pradesh, 521102, India.
authors.forename: Yathiraja Rao
authors.initials: YR
authors.lastname: Tammineni
authors.affiliation: Department of Veterinary Pharmacology and Toxicology, College of Veterinary Science, Hyderabad, 500 030, India.
authors.forename: Gopala Reddy
authors.initials: GR
authors.lastname: Alla
authors.affiliation: College of Veterinary Science, Proddatur, 516 360, India.
authors.forename: Madhava Rao
authors.initials: MR
authors.lastname: Thirtham
authors.affiliation: Department of Veterinary Pharmacology and Toxicology, NTR College of Veterinary Science, Gannavaram, Andhra Pradesh, 521102, India. gsrinivasarao0519@gmail.com.
authors.forename: G S
authors.identifier: http://orcid.org/0000-0003-4355-0531
authors.initials: GS
authors.lastname: Rao
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D001682:Biological Availability; D001711:Biotransformation; D002939:Ciprofloxacin / Q000819:agonists / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use / Q000031:analogs & derivatives; D004176:Dipyridamole / Q000494:pharmacology* / Q000627:therapeutic use; D004357:Drug Synergism; D004926:Escherichia coli / Q000187:drug effects / Q000254:growth & development / Q000276:immunology; D004927:Escherichia coli Infections / Q000097:blood / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D024841:Fluoroquinolones / Q000819:agonists / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006207:Half-Life; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D049990:Membrane Transport Modulators / Q000494:pharmacology* / Q000627:therapeutic use; D008657:Metabolic Clearance Rate; D008826:Microbial Sensitivity Tests; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011897:Random Allocation; D017208:Rats, Wistar
chemical_list: D000900:Anti-Bacterial Agents; D002939:Ciprofloxacin; D004176:Dipyridamole; D024841:Fluoroquinolones; D008070:Lipopolysaccharides; D049990:Membrane Transport Modulators; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C489542:Abcc4 protein, rat; C093087:cifran; C482199:lipopolysaccharide, E coli O55-B5