EFFECT OF RANITIDINE ON PHARMACOKINETIC PARAMETERS OF METRONIDAZOLE IN HEALTHY HUMAN VOLUNTEERS
Abstract:
Pharmacokinetics is the study of the time course of drug movement in the body during absorption, distribution, metabolism and elimination.Drug interactions are pharmacodynamic, pharmacokinetic, or clinical responses to the administration of a drugcombination that differs from the known effects of the individual drugs administered alone. The clinicalconsequences of drug interactions may be antagonistic, additive, synergistic, or idiosyncratic, resulting in treatmentfailure, increased pharmacologic effect, or toxic reactions, which may be serious or fatal. Due to the fact that mostdrugs are detoxified by the liver, the most important of the pharmacokinetic drug interactions involve drugmetabolism usually entailing the induction or inhibition of the cytochrome P450 (CYP450) enzyme system which isresponsible for oxidative-reductive metabolism. This study was undertaken to compare the effect of ranitidine on the pharmacokinetic parameters of metronidazole in saliva sample of normal healthy human volunteers by applying UV spectrophotometric analytical method for the estimation of metronidazole.This was done by preparing different concentrations of pure metronidazole in 0.1 N HCl solutions and their respective absorbance determined at 277 nm. Quality control studies (identification test, assay test, weight variation, friability test, disintegration and dissolution rate) for both ranitidine and metronidazole were carried out according to BP2009. The method of Kolawole and Ameh, 2004 was adopted and validated based on ICH guideline for this study. Both metronidazole and ranitidine tablets passed all the quality control studies and were thus found to be fit for the purpose of this study.The percentage recovery of the method was within the accepted range of 98 – 102 %. Calibration curve was linear within the range of 2.5–15 µg/ml adopted and validated. The adopted method was then employed in determining the effect of ranitidine on the pharmacokinetics parameters (Cmax, Tmax, Kab, Kel, t1/2ab, t1/2el, Cl, Vd, lag time and AUC) of metronidazole using human volunteers of 30 years and above and the study was divided into three phases with a washout period of two weeks. Both metronidazole and ranitidine used for this study were found to have the labeled active ingredient.They all passed the assay test as they were within the acceptable limits 95 – 105 %. Weight variation was conducted for both metronidazole and ranitidine and they all passed as their percentage mean deviation was less than 5 %. Similarly, both drugs passed the friability test which was less than 1%. Disintegration tests for both drugs reveals that they disintegrate in less 15 mins and also both metronidazole and ranitidine passed the dissolution rate as more than 70 % of the active ingredient was released in 30 mins. The percentage recovery of the method was within the accepted range of 98 – 102 %. Calibration curve was linear within the range of 2.5 – 15 µg/ml as the correlation coefficient was 0.9681. The regression equation was y= 0.027x + 0.002. After concurrent and delayed administration, Cmax of metronidazole was found to be statistically significant (p<0.05) at a value of 51.57 μg/ml and 36.27 μg/ml. Other pharmacokinetic parameters of metronidazole like AUC were not significantly (p < 0.05) affected by ranitidine. This finding indicates that ranitidine may influence the pharmacokinetics of metronidazole when co-administered together depending on the time of administration of the two drugs. Based on the finding the dosage of the metronidazole has to be reduced when concurrently administered with ranitidine so as to overcome the problem of toxicity due to significant increase of the drug in the systemic circulation.
EFFECT OF RANITIDINE ON PHARMACOKINETIC PARAMETERS OF METRONIDAZOLE IN HEALTHY HUMAN VOLUNTEERS