V Gangadhara N V Prasad1, Satyanarayana Achanta2, Yathiraja Rao Tammineni3, Gopala Reddy Alla1, Madhava Rao Thirtham4, G S Rao5. 1. Department of Veterinary Pharmacology and Toxicology, College of Veterinary Science, Hyderabad, 500 030, India. 2. Department of Anesthesiology, Duke University Medical Center, Durham, NC, 27701, USA. 3. Department of Veterinary Parasitology, NTR College of Veterinary Science, Gannavaram, Andhra Pradesh, 521102, India. 4. College of Veterinary Science, Proddatur, 516 360, India. 5. Department of Veterinary Pharmacology and Toxicology, NTR College of Veterinary Science, Gannavaram, Andhra Pradesh, 521102, India. gsrinivasarao0519@gmail.com.
Abstract
BACKGROUND AND OBJECTIVES: 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. 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 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. CONCLUSIONS: The results suggest that MRP4 inhibition increases the systemic exposure of ciprofloxacin in both normal and inflammatory conditions.
BACKGROUND AND OBJECTIVES: 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. 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 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. CONCLUSIONS: The results suggest that MRP4 inhibition increases the systemic exposure of ciprofloxacin in both normal and inflammatory conditions.
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