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Effect of oral activated charcoal on the pharmacokinetics of quinidine and quinine adintnistered intravenously to rabbits
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Effect of oral activated cha~oal on the phannacoHnefics of quinidine and quinine adnfinistered intravenously to rabbits Hasan *, M.M., Hassan * *, M.A. and R a w a s h d e h *, N.M. • Departmei:t of Pharmacolog). Faculty of Medicine and * * Department of Medicinal Chemistry, Faculty of Pharmacy, Jordan University of Science and Technology, Irbit~ Jordan The pharmacokinetics of quinidine and quinine following intravenous administration (10 mg/kg) with and without concurrent treatment with oral activated charcoal was studied in the rabbit. Marked differences were observed in the pbarmacokinetic parameters of quinidine and quinine. Compared to quinidine, quinine was characterized by larger volume of distribution (7.76 _+ 1.75 and 14.57 + 3.58 L / k g for quinidine and quinine, respectively), systemic clearance (2.51 +0.48 and 14.36 + 3.58 L / k g / h for quinidine and quinine, respectively), and elimination rate constant (0.33 +_0.09 and 1.05 + 0.25 h -1 for quinidine and quinine, respectively), and smaller half-life of elimination (2.20 _+0.59 and 1.22 + 0.55 h for quinidine and quinine, respectively), mean residence time (3.57 + 1.08 and 2.06 +_0.80 h for quinidine and quinine, respectively), and area under the concentration-time curve (4.10 :l: 0.70 and 1.35 _+0.90 for quinidine and quinine, respectively). Activated charcoal administered orally (15 gm) significantly decre.~.~d the serum concentrations of quinidine but not quinine. Furthermore, charcoal treatment significantly enhanced the systemic elimination of quinidine as indicated by the significant increase in Cl (36%) and decrease in d / 2 (30%), MRT and AUC (27%). By contrast, activated charcoal had no significant effect of the pharmacokinetic parameters of quinine. Differences between quinidine and quinine in respect to the effect of activated charcoal on the systemic elimination of these drugs seem at least, in part, to reside on dispositional factors. The high Cl and Vd of quinine in the rabbit are probable factors that make the effect of charcoal on the elimination of this drug not qpparent. P.fr.202 !
Population pharmacoHnetics of theophyHiL_, a NONMEM analysis Pillai, G., Miller, R. and Rambiritch, V. Department of Pharmacology, University of Durban-Westville, Private Bag )(54001, Durban. 4000, South Africa
The pharmacokinetics of theophylline was determined in smokers and non-smokers using the NONMEM computer programme (Sheiner et al., 1972). Data from a traditional pharmacokinetic study (23 subjects - approximately 15 samples per subject for each of 3 preparations under investigation) was used in order to determine adsorption rate constants (Ka) for the dosage forms used in the study. These Ka values were subsequently used in the determination of theophylfine's pharmacokinetics in the Indian asthmatic population attending R K Khan Hospital, Chatsworth, South Africa, from whom routine clinical data was available (approximately two samples per patient in each of 30 patients). The results obtained confirms that smoking has a significant influence on theophylline clearance. The pharmacokinetic parameters obtained for the Indian asthmatic population from R K Khan Hospital are in general agreement with published values of other population groups ~it,h a possible 20% lower clearance in Indian asL~matics who smoke. In addition to the above findings, this study has once more demonstrated the value of the NONMEM approach to population pharmacokinetic data analysis. However, a discrepancy in the interpretation of the NONMEM output was observed. Each NONMEM run provides in its output a value for its objective function, which is 2 times the negative logarithm of the likelihood function. Any difference of > 8 between the values of the objective function (DOBF) obtained for 2 models (general and constrained) used in testing a hypothesis indicates a significant improvement (p < 0.005) in the fit of the data and suggests that the constrained model should be accepted. It has long been claim-~:d
Effect of oral activated cha~oal on the phannacoHnefics of quinidine and quinine adnfinistered intravenously to rabbits Hasan *, M.M., Hassan * *, M.A. and R a w a s h d e h *, N.M. • Departmei:t of Pharmacolog). Faculty of Medicine and * * Department of Medicinal Chemistry, Faculty of Pharmacy, Jordan University of Science and Technology, Irbit~ Jordan The pharmacokinetics of quinidine and quinine following intravenous administration (10 mg/kg) with and without concurrent treatment with oral activated charcoal was studied in the rabbit. Marked differences were observed in the pbarmacokinetic parameters of quinidine and quinine. Compared to quinidine, quinine was characterized by larger volume of distribution (7.76 _+ 1.75 and 14.57 + 3.58 L / k g for quinidine and quinine, respectively), systemic clearance (2.51 +0.48 and 14.36 + 3.58 L / k g / h for quinidine and quinine, respectively), and elimination rate constant (0.33 +_0.09 and 1.05 + 0.25 h -1 for quinidine and quinine, respectively), and smaller half-life of elimination (2.20 _+0.59 and 1.22 + 0.55 h for quinidine and quinine, respectively), mean residence time (3.57 + 1.08 and 2.06 +_0.80 h for quinidine and quinine, respectively), and area under the concentration-time curve (4.10 :l: 0.70 and 1.35 _+0.90 for quinidine and quinine, respectively). Activated charcoal administered orally (15 gm) significantly decre.~.~d the serum concentrations of quinidine but not quinine. Furthermore, charcoal treatment significantly enhanced the systemic elimination of quinidine as indicated by the significant increase in Cl (36%) and decrease in d / 2 (30%), MRT and AUC (27%). By contrast, activated charcoal had no significant effect of the pharmacokinetic parameters of quinine. Differences between quinidine and quinine in respect to the effect of activated charcoal on the systemic elimination of these drugs seem at least, in part, to reside on dispositional factors. The high Cl and Vd of quinine in the rabbit are probable factors that make the effect of charcoal on the elimination of this drug not qpparent. P.fr.202 !
Population pharmacoHnetics of theophyHiL_, a NONMEM analysis Pillai, G., Miller, R. and Rambiritch, V. Department of Pharmacology, University of Durban-Westville, Private Bag )(54001, Durban. 4000, South Africa
The pharmacokinetics of theophylline was determined in smokers and non-smokers using the NONMEM computer programme (Sheiner et al., 1972). Data from a traditional pharmacokinetic study (23 subjects - approximately 15 samples per subject for each of 3 preparations under investigation) was used in order to determine adsorption rate constants (Ka) for the dosage forms used in the study. These Ka values were subsequently used in the determination of theophylfine's pharmacokinetics in the Indian asthmatic population attending R K Khan Hospital, Chatsworth, South Africa, from whom routine clinical data was available (approximately two samples per patient in each of 30 patients). The results obtained confirms that smoking has a significant influence on theophylline clearance. The pharmacokinetic parameters obtained for the Indian asthmatic population from R K Khan Hospital are in general agreement with published values of other population groups ~it,h a possible 20% lower clearance in Indian asL~matics who smoke. In addition to the above findings, this study has once more demonstrated the value of the NONMEM approach to population pharmacokinetic data analysis. However, a discrepancy in the interpretation of the NONMEM output was observed. Each NONMEM run provides in its output a value for its objective function, which is 2 times the negative logarithm of the likelihood function. Any difference of > 8 between the values of the objective function (DOBF) obtained for 2 models (general and constrained) used in testing a hypothesis indicates a significant improvement (p < 0.005) in the fit of the data and suggests that the constrained model should be accepted. It has long been claim-~:d