Effect of Multi Drug Resistance Protein 4 (MRP4) Inhibition on the Pharmacokinetics and Pharmacodynamics of Ciprofloxacin in Normal and Rats with LPS-Induced Inflammation.

Published

Journal Article

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 (C max/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.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.Induction of inflammation in rats resulted in marked reduction in C max and AUC; and an increase in the volume of distribution (V d/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 V d/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.The results suggest that MRP4 inhibition increases the systemic exposure of ciprofloxacin in both normal and inflammatory conditions.

Full Text

Duke Authors

Cited Authors

  • Prasad, VGNV; Achanta, S; Tammineni, YR; Alla, GR; Thirtham, MR; Rao, GS

Published Date

  • December 2016

Published In

Volume / Issue

  • 41 / 6

Start / End Page

  • 733 - 741

PubMed ID

  • 26458556

Pubmed Central ID

  • 26458556

Electronic International Standard Serial Number (EISSN)

  • 2107-0180

International Standard Serial Number (ISSN)

  • 0378-7966

Digital Object Identifier (DOI)

  • 10.1007/s13318-015-0302-5

Language

  • eng