Philip D. Worboys

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The objective of the present study was to examine the accuracy of using unbound brain concentration determined by a brain homogenate method (C(ub)), cerebral spinal fluid concentration (C(CSF)), and unbound plasma concentration (C(up)) as a surrogate for brain interstitial fluid concentration determined by brain microdialysis (C(m)). Nine(More)
The time course for distribution of five compounds (caffeine, tolbutamide, phenytoin, ondansetron, and diazepam) was studied in precision-cut rat liver slices. Transport of these compounds differed greatly, with caffeine being distributed rapidly, but not accumulating above the media concentration. Although tolbutamide similarly was not accumulated within(More)
The kinetics of metabolism of diazepam, phenytoin, and caffeine have been determined in rat liver slices of 260 microns thickness. The formation of 4'-hydroxy metabolites of diazepam and phenytoin are described by one- and two-site Michaelis-Menten equations, respectively. The other oxidative pathways for diazepam are less readily saturable than the(More)
Ethoxycoumarin (EC) and tolbutamide (TOL) were selected as examples of high- and low-clearance drugs, respectively, to investigate suitable methodologies for obtaining kinetic data on metabolism by precision-cut rat liver slices. A number of characteristics of the slice incubation were compound-dependent. TOL showed linear rates of metabolism over a longer(More)
1. Enzyme induction has traditionally been studied during drug development to assess the potential of drug entities to interact with concomitant medications and alter their pharmacological effects, and clearly it is an unwanted phenomenon. However, another hurdle caused by induction occurs during preclinical development via the attainment of safety data,(More)
A population pharmacokinetic model of telavancin, a lipoglycopeptide antibiotic, was developed and used to identify sources of interindividual variability. Data were obtained from healthy subjects (seven phase 1 studies), patients with complicated skin and skin structure infections (cSSSI; two phase 2 and two phase 3 studies), and patients with(More)
Aliphatic nitrogen heterocycles such as piperazine, piperidine, pyrrolidine, morpholine, aziridine, azetidine, and azepane are well known building blocks in drug design and important core structures in approved drug therapies. These core units have been targets for metabolic attack by P450s and other drug metabolizing enzymes such as aldehyde oxidase and(More)
1. The kinetics of hydroxylation and N-demethylation of ondansetron have been determined in freshly isolated hepatocytes, hepatic microsomes and precision-cut liver slices from the male Sprague-Dawley rat. In vivo studies have also been carried out to characterize the pharmacokinetics of ondansetron and in vitro data have been assessed for their value as(More)
1. The metabolism of 2,5-bis(trifluoromethyl)-7-benzyloxy-4-trifluoromethylcoumarin (BFBFC) to 7-hydroxy-4-trifluoromethylcoumarin (HFC) was studied in human liver microsomes and in cDNA-expressed human liver CYP isoforms. For purposes of comparison, some limited studies were also performed with 7-benzyloxyquinoline (7BQ). 2. Initial interactive docking(More)
Telavancin is a semisynthetic lipoglycopeptide with a dual mechanism of action against Gram-positive pathogens. Two brief reports have suggested potential cross-reactivity of telavancin with the vancomycin particle-enhanced turbidometric immunoassay (PETIA). The purpose of this study was to evaluate several commercially available vancomycin immunoassays(More)