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F Khorasheh

Publications and source records attributed to F Khorasheh.

2 recordsLinked to original sources
PubMed1999

Dependency of gastrointestinal toxicity on release rate of tiaprofenic acid: a novel pharmacokinetic-pharmacodynamic model.

PURPOSE: To test the hypothesis that modification of release pattern of nonsteroidal anti-inflammatory drugs (NSAIDs) formulations shifts gastrointestinal (GI) toxicity of the drugs from the upper GI region to the distal intestine. METHODS: We assessed tiaprofenic acid (TA)-induced upper and lower increased GI permeability (a surrogate marker of toxicity) after administration of 20 mg and 40 mg/kg regular release (powder) and modified release formulations [sustained release (SR) beads and diethyl-beta-cyclodextrin (DCD):TA inclusion complex (INC)]. Urinary excretion of oral doses of GI permeability probes sucrose and 51Cr-EDTA was determined as measures of gastroduodenal and distal intestine, respectively. Pharmacokinetics of TA enantiomers were also studied following administration of a single 20 mg/kg dose of racemic TA as oral SR beads and iv solution. For powder and INC, previously reported pharmacokinetic data were used. RESULTS: Regular powder significantly increased the permeability at the gastroduodenal level. Modified-release formulations, on the other hand, did not cause damage in the gastroduodenum but produced significant increase in the permeability of the lower intestine. Consequently, to assess the pharmacokinetic-pharmacodynamic relationship, a new model was developed in which contribution of toxicity resulted from direct exposure to the drug was considered. CONCLUSIONS: Since the observed site of GI damage corresponds to the site of release and absorption of NSAID from the formulation, the possibility of a shift in the site of damage must be considered for the modified release formulations. A parallel evaluation of upper and lower GI toxicity is essential for a complete assessment of NSAID-induced GI damage.

Administration, Oral↗
PubMedDate not supplied

Application of direct search optimization for pharmacokinetic parameter estimation.

PURPOSE: For simple pharmacokinetic compartmental models, analytical solution to the governing differential equations along with common graphical methods provide a mean to evaluate the associated rate constants. These graphical methods, however, can not be used for the more complex multi-compartment models. Furthermore, parameter estimation using slope and intercept values from the graphical methods is often accompanied with error. In this study a numerical solution is applied for the solution of the governing differential equations and a simple direct search optimization procedure utilizing random numbers is used for pharmacokinetic parameter estimation. METHOD: The methodology is demonstrated with reference to experimental literature data for ciprofloxacin and ofloxacin whose pharmacokinetic behavior has been reported in terms of a two-compartment model. RESULTS: Examination of the predicted drug concentrations from the graphical method and the optimization methodology indicate that both methods have comparable accuracy in predicting the drug concentrations. The graphical method, however, only shows good accuracy in the early stages both after i.v. and oral drug administration whereas the optimization procedure, due to the nature of the objective function formulation, provides good accuracy over the entire range of times after drug administration. CONCLUSIONS: The methodology is simple, provides optimized parameters which accurately predict drug concentrations, and is flexible to include more weight on the early-time data or be extended to multi-compartment models.

Adult↗