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Two-compartmental Model (two-compartmental + model)
Selected AbstractsBioavailability and pharmacokinetic model for ritonavir in the ratJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 3 2007R. Lledó-García Abstract The aim of this study is to investigate in vivo the oral bioavailability of ritonavir and to evaluate the pharmacokinetic model that best describes the plasma concentration behavior after oral and intravenous administration. Male Wistar rats were intravenously administered at 3 mg dose of pure ritonavir and oral administered at 4.6,±,2.5 mg of diluted Norvir®. Blood samples were taken by means of the jugular vein for a 24 h period of time. An analytical high-performance liquid chromatography (HPLC) technique was developed in order to quantify ritonavir plasma concentrations. A nonlinear modeling approach was used to estimate the pharmacokinetic parameters of interest. Results showed that a two-compartmental model with zero-order kinetic in the incorporation process of ritonavir into the body better fitted intravenous and oral data. The estimated oral bioavailability by means of noncompartmental and compartmental approaches resulted in 74% and 76.4%, respectively. These values confirm the ones obtained by other authors in the rat. In conclusion, a zero-order kinetic in the incorporation process at the administered doses suggests the saturation of the possible specialized transport mechanisms involved in the incorporation of ritonavir into the body. These results could justify the use of low doses of ritonavir when improving the bioavailability of other protease inhibitors (PIs) is required. © 2006 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci [source] In vivo release of oxytetracycline from a biodegradable controlled-release gel injected subcutaneously in Japanese quail (Coturnix coturnix japonica)JOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 4 2003L. A. Tell A long-acting, biodegradable, controlled-release formulation of oxytetracycline (CR-OTC) was evaluated in 18 adult Japanese quail (Coturnix coturnix japonica) following a single subcutaneous (s.c.) injection. Prior to characterizing the release of oxytetracycline (OTC) from the CR-OTC, the pharmacokinetic parameters of intravenously (i.v.) administered OTC were determined. Concentrations of free OTC were measured using a bioassay. The plasma concentration,time profile of OTC after a single i.v. injection at 20 mg/kg was best fit to an open two-compartmental model, with the following pharmacokinetic parameters: area under the curve (AUC) = 36.72 mg · h/L, terminal elimination half-life = 2.34 h, clearance (Cl) = 0.545 L/kg/h. Plasma [OTC] was >1.0 ,g/mL for at least 4 h following i.v. injection. The CR-OTC gel was well tolerated at a dosage of 1500 mg/kg s.c. Plasma [OTC] rose to >1.0 ,g/mL within 24 h; it remained >1.0 ,g/mL for at least 10 days in all birds sampled at that time point (n = 9) and for at least 18 days in two of nine birds. Using a deconvolution technique, it was determined that approximately 54.8% of the administered OTC was released from the CR-OTC over the 45-day observation period. This long-acting, biodegradable controlled-release OTC formulation may have potential for the treatment of chlamydophila infections and other OTC-sensitive bacteria in Japanese quail, however further studies are necessary to determine its safety and clinical application. [source] Pharmacokinetics and analgesic effects of intravenous propacetamol vs rectal paracetamol in children after major craniofacial surgeryPEDIATRIC ANESTHESIA, Issue 7 2008SANDRA A. PRINS MD PhD Summary Background:, The pharmacokinetics and analgesic effects of intravenous and rectal paracetamol were compared in nonventilated infants after craniofacial surgery in a double-blind placebo controlled study. Methods:, During surgery all infants (6 months,2 years) received a rectal loading dose of 40 mg·kg,1 paracetamol 2 h before anticipated extubation. On admittance to the pediatric surgical ICU, the children were randomized to receive either a 15 min intravenous infusion of 40 mg·kg,1 propacetamol, a prodrug of paracetamol, or 20 mg·kg,1 paracetamol rectally every 6 h. A population pharmacokinetic analysis of the paracetamol plasma concentration time-profiles was undertaken using nonlinear mixed effects models. The visual analogue scale (VAS) (score 0,10 cm) and COMFORT Behavior scale (score 6,30) were used to monitor analgesia in the 24-h period following surgery. Results:, Twelve infants received intravenous propacetamol and 14 paracetamol suppositories. Paracetamol pharmacokinetics were described according to a two-compartmental model with linear disposition. Pharmacokinetic parameters were standardized to a 70 kg person using allometric ,1/4 power' models. Parameter estimates were: absorption half-life from the rectum 4.6 h, propacetamol hydrolysis half-life 0.028 h, clearance 12 l·h,1·70 kg,1, intercompartmental clearance 116 l·h,1·70 kg,1, central and peripheral volume of distribution 7.9 and 44 l·70 kg,1, respectively. During the 24-h study period 22 infants exhibited VAS scores <4 cm, which was considered a cutoff point. On single occasions four patients, two in each group, exhibited a VAS score ,4 cm. Nine patients in the rectal treatment group and three patients in the intravenous treatment group received midazolam for COMFORT-B scores exceeding 17 (P < 0.05). Conclusions:, Intravenous propacetamol proved to be more effective than rectal paracetamol in infants after craniofacial surgery. Midazolam was more frequently administered to patients receiving paracetamol suppositories, indicating that these children experienced more distress, possibly caused by pain. [source] Application of lag-time into exposure definitions to control for protopathic bias,PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, Issue 3 2007H. Tamim Abstract Purpose To control for protopathic bias, some studies have incorporated the concept of lag-time into their exposure definition (time period before the index date that was not considered in assessing exposure). The objective of this study was to introduce a procedure to identify the best lag-time to be applied in studies where control for protopathic bias is required. Methods We used data from a case-control study carried out to assess the association between exposure to proton pump inhibitors (PPIs) and risk of gastric cancer, using RAMQ databases. Exposure was defined as the number of defined daily doses of PPIs dispensed during the 5-year period prior to the index date (divided into four quartiles). Thirty-one different lag-times were applied (0,30 months) based on 1-month intervals. Logistic regression was used to estimate the matched odds ratio (OR) for each lag-time. The change point in the ln(ORs) was identified by applying a two-compartmental model and a segmented regression model. Results A trend of decreasing ORs was found with the application of an increasing lag-time. As an illustration, the ORs for the 1st quartile of defined daily doses, when applying the 31 different lag-times, ranged between 3.52 when applying a 0 lag-time and 0.97 when applying a 30 months lag-time. Applying the two methods for the different lag-times showed that the ORs stabilized at around 6 months. Conclusion For the purpose of controlling for protopathic bias in pharmacoepidemiological studies, we have provided a method to assess the most appropriate lag-time that should be applied for the assessment of drug exposure. Copyright © 2007 John Wiley & Sons, Ltd. [source] Determination of unbound cefamandole in rat blood by microdialysis and microbore liquid chromatographyBIOMEDICAL CHROMATOGRAPHY, Issue 1 2001Pen-Ho Yeh To analyze unbound cefamandole in rat blood, a method combing microdialysis with microbore liquid chromatography has been developed. A microdialysis probe was inserted into the jugular vein/right atrium of male Sprague,Dawley rats to examine the unbound cefamandole level in the rat blood following cefamandole administration (50,mg/kg, i.v.). The dialysates were directly submitted to a liquid chromatographic system. Samples were eluted with a mobile phase containing acetonitrile,methanol,100,mM monosodium phosphate (pH 5.0; 15:20:65, v/v). The UV wavelength was set at 270,nm for monitoring the analyte. Using the retrograde method, at infusion concentrations of 1,µg/mL of cefamandole, the in vivo microdialysis recoveries were 55.44% for the rat blood (n,=,6). Intra- and inter-assay accuracy and precision of the analyses were ,10% in the range of 0.1,10,µg/mL. Pharmacokinetic parameters were calculated from the recovery-corrected dialysate concentrations of cefamandole vs time data. The elimination half-life (t1/2,,) was 21.6,±,1.6,min. The results suggest that the pharmacokinetics of unbound cefamandole in blood following cefamandole administration (50,mg/kg, i.v., n,=,5) fit best to the two-compartmental model. Copyright © 2001 John Wiley & Sons, Ltd. Abbreviations used: RSD relative standard deviation [source] | |||||||||||||