Graduate Thesis Or Dissertation
 

Analysis of nonlinear pharmacokinetic systems and the nonlinear disposition of phenylbutazone in equine (horses)

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https://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/r494vp69w

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  • The first part of the dissertation is to evaluate the use of proposed and established equations for area under the plasma concentration versus time (AUC) for molecules undergoing nonlinear Michaelis–Menten pharmacokinetic elimination. The effects of varying Michaelis-Menten parameters, rate of drug absorption, or bioavailability on the predictability of drug exposure (AUC) for single-dose data were performed by computer simulation for one- compartment model with first-order drug absorption and two- compartment model with i.v.-bolus administration. Results show that the use of our proposed equation for one-compartment 1st-order absorption model is adequate in most cases of dose, k[subscript a] and clearance ratio. The use of the established equation for two-compartment i.v. model, however, was indentified to be limited under low doses and high clearance ratio (V[subscript m]/K[subscript m]). The second part is to study the potential drug interaction between Phenylbutazone and Ranitidine in thoroughbred horses. Pharmacokinetic study was conducted in a cross-over design in which the horses received co-administration of ranitidine or control treatment. The study started with single-dose oral administrations of 2.2, 4.4, and 8.8 mg/kg phenylbutazone, and then multiple-dose administrations 2.2, 4.4, and 8.8 mg/kg phenylbutazone with a 1-week washout period between trials. Neither plasma concentration profiles nor the observed pharmacokinetic parameters of phenylbutazone were significantly altered by ranitidine treatment. The results suggest that concurrent treatment with ranitidine and phenylbutazone does not result in elevations of plasma phenylbutazone concentrations. Ranitidine should be safe to be co-administered with phenylbutazone in thoroughbred horses. The third part is about two pharmacokinetic studies investigating O,O-dimethylphosphate (DMP) and xanthohumol (XN) respectively, in Male Sprague-Dawley rats. Levels of urinary dialkylphosphates (DAPs) are currently used as a biomarker of human exposure to organophosphorus insecticides (OPs). It is known that OPs degrade on food commodities to DAPs at levels that approach or exceed those of the parent OP. However, little has been reported on the extent of DAP absorption, distribution, metabolism and excretion. Rats were administered DMP at 20 mg/kg via oral gavage and I.V. injection. DMP bioavailability was found to be 107 ± 39 % and the amount of the orally administered dose recovered in the urine was 30 ± 9.9 % by 48 hrs. The in vitro metabolic stability, high bioavailability and extent of DMP urinary excretion following oral exposure in a rat model suggests that measurement of DMP as a biomarker of insecticide exposure may lead to overestimation of human exposure. Xanthohumol (XN) is a dietary flavonoid found in hops showing health protective actions against cardiovascular disease and type 2 diabetes. This study provides basic pharmacokinetics (PK) parameters for XN and its major metabolites in rats. The maximum concentration (C[subscript max]) and area under the curve (AUC[subscript 0-∞]) of total XN (free and conjugated) were 2.9 ± 0.1 mg/L and 2.5 ± 0.3 h*mg/L in the IV group, 0.019 ± 0.002 mg/L and 0.84 ± 0.17 h*mg/L in the oral low group, 0.043 ± 0.002 mg/L and 1.03 ± 0.12 h*mg/L in the oral medium group, and 0.15 ± 0.01 mg/L and 2.49 ± 0.10 h*mg/L in the oral high group. The bioavailability of XN is dose-dependent and approximately 0.33, 0.13 and 0.11 in rats, for the low, medium and high dose groups, respectively.
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