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What is known and Objective: Rifampicin (RIF) shows wide variability in its pharmacokinetics. The purpose of this study was to develop and validate a population pharmacokinetic model to characterize the inter- and intra-individual variability in pharmacokinetic parameters of RIF in Mexican patients. Methods: Ninety-four patients receiving antituberculosis therapy participated in this prospective study. Plasma concentration-time data were described using a one-compartment model with lag time, absorption and first-order elimination. The potential influence of demographic and clinical characteristics of the patients, and the pharmaceutical formulation (A, B, C and D) on the pharmacokinetics parameters, was evaluated by non-linear mixed-effect modelling ( nonmem). Seventy-seven additional patients participated in the validation of the model. Results and Discussion: The final population pharmacokinetic model obtained was as follows: apparent clearance CL/ F = 8·17 L/h (1·40 as high for males), apparent distribution volume Vd/ F = 50·1 L (1·29 as high for males), absorption rate constant KaA = 0·391/h, KaB,C,D = 2·70/h, relative bioavailability FA = 0·468, FB,C,D = 1, lag time in the absorption phase Tlag = 0·264 h. The final model improved the precision on the parameter estimates (CL/ F, Vd/ F and Ka by 31·9%, 16·7% and 92·9%, respectively). The residual variability was 27·3%. What is new and Conclusion: Gender was associated with changes in CL/ F and Vd/ F whereas the pharmaceutical formulation was associated with changes in F and altered the Ka. The validation data set showed that the model could be used in clinical practice for Bayesian dose adjustment of RIF in TB patients. [ABSTRACT FROM AUTHOR]

The physicochemical properties, p Ka, Log P and solubility of compound alpha, (5-chloro-2-(methylthio)-6-(1-naphthyloxy)-1 H-benzimidazole), a new fasciolicide agent, were characterized using conventional methods. Also, its pharmacokinetics was evaluated in sheep and cattle. In both species an oral dose of 12 mg/kg was administered. Blood samples were collected during 144 h and analyzed by using an HPLC assay. Results showed that compound alpha is a weak base with a p Ka value of 2.87 and log P of 1.44. The solubility was very low in aqueous solvents. Pharmacokinetic studies showed that in both species compound alpha could not be detected at any sampling time. The mean half-life ( t½) values of alpha sulphoxide in sheep and cattle were 19.86 and 29.87 h, while the half-life values of alpha sulphone were 19.43 and 46.32 h respectively. Cmax values of alpha sulphoxide did not differ between species while alpha sulphone values were higher in cattle. Plasma protein binding of alpha sulphoxide was between 82% and 86%. These results, combined with the previous efficacy studies, suggest that compound alpha could be a promising fasciolicide agent. [ABSTRACT FROM AUTHOR]

Good manufacturing practices specify that a well-type scintillation NaI(Tl) crystal detector has to be validated in order to detect radioactivity from any radiopharmaceutical used to obtain radiopharmacokinetic parameters. A 5 cm well-type NaI(Tl) scintillation detector was coupled to a multi-channel analyzer centered at the 140 keV 99mTc peak with a 20% window. The area represents counts per minute (cpm). All the net cpm were decay corrected. The activity source was 99mTc-glucarate developed as an imaging agent for acute myocardial infarction. Wistar rats were injected in a tail vein with 0.1 ml (3.7 MBq) of 99mTc-glucarate solution and 13 blood samples were taken. The cpm were the input data for the WINNONLN program which calculates radiopharmacokinetic parameters. The detector's efficiency for 99mTc was 15.03% and the sensitivity 1.12 kBq/ml in plasma. The response was linear between 0.31-14.3 kBq/ml of 99mTc-glucarate. The maximum assay variation coefficient was 2.79 and recovery of 99mTc-glucarate in plasma was 99.8%±0.2%. LOD was 0.31 kBq and LOQ = 1.12 kBq in plasma samples. 99mTc-glucarate follows a two-compartment model of distribution with Vd of 21.74 ml±2.71 ml; a Vdss of 74.36 ml±12.67 ml; t1/2a 0.74 h±0.19 h; t1/2b 18.98 h±4.36 h; AUC = 32.75 mCi/min.ml ± 3.73 mCi/min.ml; MRT = 24.35 h±5.51 h and total clearance 3.05 ml/h±0.35 ml/h. The well-type detector fulfills the quality system requirements and the radiopharmacokinetic parameters for 99mTc-glucarate in rats are reliable. [ABSTRACT FROM AUTHOR]