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Preclinical Pharmacokinetics (preclinical + pharmacokinetic)
Selected AbstractsPreclinical pharmacokinetics and metabolism of 6-(4-(2,5-difluorophenyl)oxazol-5-yl)-3-isopropyl-[1,2,4]-triazolo[4,3- a]pyridine, a novel and selective p38, inhibitor: identification of an active metabolite in preclinical species and human liver microsomesBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 8 2006Amit S. Kalgutkar Abstract The disposition of 6-(4-(2,5-difluorophenyl)oxazol-5-yl)-3-isopropyl-[1,2,4]-triazolo[4,3- a]pyridine (1), a potent and selective inhibitor of mitogen activated protein (MAP) kinase p38,, was characterized in several animal species in support of its selection for preclinical safety studies and potential clinical development. 1 demonstrated generally favorable pharmacokinetic properties in all species examined. Following intravenous (i.v.) administration, 1 exhibited low volumes of distribution at steady state (Vdss) ranging from 0.4,1.3 l/kg (2.4,26 l/m2) in the rat, dog and monkey. Systemic plasma clearance was low in cynomolgus monkeys (6.00 ml/min/kg, 72.0 ml/min/m2) and Sprague-Dawley rats (7.65±1.08 ml/min/kg, 45.9±6.48 ml/min/m2 in male rats and 3.15±0.27 ml/min/kg, 18.9±1.62 ml/min/m2 in female rats) and moderate in beagle dogs (12.3±5.1 ml/min/kg, 246±102 ml/min/m2) resulting in plasma half-lives ranging from 1 to 5 h in preclinical species. Moderate to high bioavailability of 1 was observed in rats (30,65%), dogs (87%) and monkeys (40%) after oral (p.o.) dosing consistent with the in vitro absorption profile of 1 in the Caco-2 permeability assay. In rats, the oral pharmacokinetics were dose dependent over the dose range studied (5, 50 and 100 mg/kg). The principal route of clearance of 1 in rat, dog, monkey and human liver microsomes and in vivo in preclinical species involved oxidative metabolism mediated by cytochrome P450 enzymes. The major metabolic fate of 1 in preclinical species and humans involved hydroxylation on the isopropyl group to yield the tertiary alcohol metabolite 2. In human liver microsomes, this transformation was catalysed by CYP3A4 as judged from reaction phenotyping analysis using isozyme-specific inhibitors and recombinant CYP enzymes. Metabolite 2 was also shown to possess inhibitory potency against p38, in a variety of in vitro assays. 1 as well as the active metabolite 2 were moderately to highly bound to plasma proteins (fu,0.1,0.33) in rat, mouse, dog, monkey and human. 1 as well as the active metabolite 2 did not exhibit competitive inhibition of the five major cytochrome P450 enzymes namely CYP1A2, 2C9, 2C19, 2D6 and 3A4 (IC50>50 µM). Overall, these results indicate that the absorption, distribution, metabolism and excretion (ADME) profile of 1 is relatively consistent across preclinical species and predict potentially favorable pharmacokinetic properties in humans, supporting its selection for toxicity/safety assessment studies and possible investigations in humans as an anti-inflammatory agent. Copyright © 2006 John Wiley & Sons, Ltd. [source] Development of a liquid chromatography/tandem mass spectrometry assay for the quantification of PM02734, a novel antineoplastic agent, in dog plasmaRAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 18 2006Jianming Yin A rapid and sensitive liquid chromatography/tandem mass spectrometry (LC/MS/MS) assay was developed and validated to quantify a novel antineoplastic agent, PM02734, in dog plasma. The method was validated to demonstrate the specificity, limit of quantification (LOQ), accuracy, and precision of measurements. The calibration range for PM02734 was established using PM02734 standards from 0.05 to 100,ng/mL in blank plasma. The dominating ions were doubly charged molecular ions [M+2H]2+ at m/z 740.0 instead of singly charged ones at m/z 1478.4. The selected reaction monitoring (SRM), based on the m/z 740.0,,,212.2 transition, was specific for PM02734, and that based on the m/z 743.8,,,212.2 transition was specific for deuterated PM02734 (the internal standard, IS); no endogenous materials interfered with the analysis of PM02734 and IS from blank plasma. The assay was linear over the concentration range 0.05,100,ng/mL. In terms of sensitivity of assay 0.05,ng/mL is a very low LLOQ, especially considering PM02734 is a peptide. The correlation coefficients for the calibration curves ranged from 0.9990 to 0.9999. The mean intraday and interday accuracies for all calibration standards (n,=,9) ranged from 93 to 111% (,11% bias) in dog plasma, and the mean interday precision for all calibration standards was less than 6.4%. The mean intra- and interday assay accuracy for all quality control replicates in dog plasma (n,=,9), determined at each QC level throughout the validated runs, ranged from 85,111% (,15% bias) and from 99,109% (,9% bias), respectively. The mean intra- and interday assay precision was less than 12.1 and 13.3% for all QC levels, respectively. The assay has been used to support preclinical pharmacokinetic (PK) and toxicokinetic studies. The results showed that preclinical samples could be monitored for PM02734 up to 168,h after dosing, which allowed us to identify multiple elimination phases and accurately estimate PK information. Copyright © 2006 John Wiley & Sons, Ltd. [source] Liquid chromatographic,mass spectrometry analysis and pharmacokinetic studies of a novel rabeprazole formulation, sterile powder for injection, in dogs and ratsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 4 2007Feng Shao Abstract Rabeprazole is among the most potent proton pump inhibitors (PPI) identified to date and it has been demonstrated that it is effective in such diseases as gastroesophageal reflux disease (GERD), duodenal ulcer and gastric ulcer. There is currently interest in developing a new formulation: rabeprazole sterile powder for injection (RSPI). This investigation was conducted to evaluate the preclinical pharmacokinetics of RSPI in rats and at the same time a comparative study was carried out in dogs between RSPI and Pariet® tablets using liquid chromatographic,mass spectrometry analysis. The liquid chromatographic,mass spectrometry method was first conducted and validated as being specific, and having accuracy, precision, sensitivity and a satisfactory recovery. After intravenous administration of RSPI (i.v.: 2, 6 and 18 mg/kg) to rats, no significant dose-dependency was found in the CL (4.20,5.72 l/h/kg), Varead (0.94,1.32 l/kg), dose-normalized AUC (197.20,245.82 µg/l*h based on 1 mg/kg) and t1/2 (p>0.05). In the dog, a randomized, open-label, crossover experiment was carried out to show that the mean area under the plasma concentration-time curve (AUC0,,) after i.v. administration of RSPI was at least four times larger than that following oral administration of Pariet® tablet at an equivalent dose but the elimination half-life of these two formulation was similar (p>0.05). The results showed that the pharmacokinetics of RSPI was linear (r2 = 0.98) in the dose range 2,18 mg/kg and the RSPI had a much higher AUC0,, and similar t1/2 values compared with the enteric-coated tablet. Copyright © 2007 John Wiley & Sons, Ltd. [source] Pharmacokinetics of SB-247083, a potent and selective endothelinA receptor antagonist, in the rat, dog, and monkeyBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 8 2002Keith W. Ward Abstract The endothelins (ET) are among the most potent vasoconstrictors identified to date, and have been implicated in such diseases as renal failure, pulmonary hypertension, atherosclerosis, and congestive heart failure. There is currently interest in developing selective antagonists of the ET-A subtype receptor, and one such antagonist is SB-247083 ((E)-[1-butyl-5-[2-(2-carboxyphenyl) methoxy-4-chlorophenyl]-1H-pyrazole-4-yl]-2-[5-methoxydihydrobenzofuran-6-yl]methyl]-2-propionic acid). This investigation was conducted to evaluate the preclinical pharmacokinetics of SB-247083. Clearance of SB-247083 was low to moderate in the rat and monkey, and high in the dog. Oral bioavailability of SB-247083 administered as a solid formulation of the free acid was 24% in the rat, but low in the dog (4%) and the monkey (2%). An extensive in vitro salt form and formulation screen resulted in the identification of a formulation containing the monoarginyl salt with improved dissolution properties. This formulation provided a 2- to 4-fold increase in oral bioavailability in each of the preclinical species. In the dog, this improvement was reversed by the pre-administration of 0.1 N HCl to normalize the achlorhydric fasting dog stomach. These data show that SB-247083 may have suitable drug properties for progression in development. Copyright © 2002 John Wiley & Sons, Ltd. [source] The experimental Alzheimer drug phenserine: preclinical pharmacokinetics and pharmacodynamicsACTA NEUROLOGICA SCANDINAVICA, Issue 2000N. H. Greig Phenserine, a phenylcarbamate of physostigmine, is a new potent and highly selective acetylcholinesterase (AChE) inhibitor, with a >50-fold activity versus butyrylcholinesterase (BChE), in clinical trials for the treatment of Alzheimer's disease (AD). Compared to physostigmine and tacrine, it is less toxic and robustly enhances cognition in animal models. To determine the time-dependent effects of phenserine on cholinergic function, AChE activity, brain and plasma drug levels and brain extracellular acetylcholine (ACh) concentrations were measured in rats before and after phenserine administration. Additionally, its maximum tolerated dose, compared to physostigmine and tacrine, was determined. Following i.v. dosing, brain drug levels were 10-fold higher than those achieved in plasma, peaked within 5 min and rapidly declined with half-lives of 8.5 and 12.6 min, respectively. In contrast, a high (>70%) and long-lasting inhibition of AChE was achieved (half-life >8.25 h). A comparison between the time-dependent plasma AChE inhibition achieved after similar oral and i.v. doses provided an estimate of oral bioavailability of 100%. Striatal, in vivo microdialysis in conscious, freely-moving phenserine-treated rats demonstrated >3-fold rise in brain ACh levels. Phenserine thus is rapidly absorbed and cleared from the body, but produces a long-lasting stimulation of brain cholinergic function at well tolerated doses and hence has superior properties as a drug candidate for AD. It selectively inhibits AChE, minimizing potential BChE side effects. Its long duration of action, coupled with its short pharmacokinetic half-life, reduces dosing frequency, decreases body drug exposure and minimizes the dependence of drug action on the individual variations of drug metabolism commonly found in the elderly. [source] | ||||||||||