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Biomedical subjects

S Toon

Publications and source records attributed to S Toon.

At least 37 records · Page 2Linked to original sources
PubMed1990

Investigations into the potential effects of multiple dose ketorolac on the pharmacokinetics and pharmacodynamics of racemic warfarin.

1. The potential interaction between racemic warfarin given as a 25 mg single oral dose and chronically administered ketorolac was studied in 12 young healthy male volunteers. 2. Ketorolac produced no major change in the pharmacokinetics of (R)- or (S)-warfarin. 3. Ketorolac did not alter the pharmacodynamic profile of racemic warfarin. 4. Ketorolac increased template bleeding time by a factor of 1.35 as compared with placebo. 5. The results suggest that the ketorolac-warfarin interaction is unlikely to be of major clinical significance; however, combined use of ketorolac and warfarin in patients should be undertaken with due caution and appropriate monitoring.

Adult↗
PubMed1989

Rate and extent of absorption of clonidine from a transdermal therapeutic system.

The in-vivo performance of a clonidine transdermal therapeutic system (TTS 3.5 cm2, 2.5 mg) was assessed in 12 healthy normal volunteers. Particular attention was paid to the rate and extent of absorption of clonidine from the TTS dosage form by reference to a 2 h i.v. infusion of clonidine. The absolute bioavailability of clonidine from the TTS dosage form was found to be approximately 60% with clonidine being released from the TTS at a relatively reproducible and consistent rate of 4.32 micrograms h-1 over a 7-day period.

Absorption↗
PubMed1988

The racemic metoprolol H2-antagonist interaction.

The effects of concomitant administration of cimetidine and ranitidine on the pharmacokinetics and pharmacodynamics of multiple-dose metoprolol were investigated in 12 normal, healthy male volunteers. The pharmacokinetics of metoprolol were assessed in terms of racemic metoprolol and the individual (R)- and (S)-enantiomers with a stereoselective assay. Ranitidine had no effect on the pharmacodynamics or pharmacokinetics of metoprolol. Although not affecting the pharmacodynamics of metoprolol, cimetidine did produce an increase in the bioavailability of metoprolol through inhibition of enzymes responsible for the first-pass elimination of the beta-blocker. The effect was stereoselective, with the major effect being on the less pharmacologically active (R)-enantiomer.

Adult↗
PubMed1988

A study to assess the anticholinergic activity of rolipram in healthy elderly volunteers.

Rolipram is an antidepressant with a novel mechanism of action: enhanced noradrenaline (first messenger) synthesis and release, and inhibition of cAMP (second messenger) breakdown. This study was aimed at objectively assessing potential anticholinergic effects of rolipram in healthy elderly volunteers by measurement of saliva production and pupil size. Eight male volunteers between 67 and 77 years of age first received in a randomized manner either a single dose of 50 mg amitriptyline or a placebo control. After a minimum washout period of seven days, they then received a multiple dosing regimen of a) 0.75 mg and b) 1.5 mg rolipram given every eight hours over a 5-day period with a two day washout between a) and b). Whereas no changes at all in pupil size could be observed, amitripyline significantly reduced salivary flow. Rolipram however had no effect on saliva production after either single or repeated administration of 0.75 or 1.5 mg. The results are discussed in connection with pharmacokinetic parameters obtained in the study.

Aged↗
PubMed1987

Comparative effects of ranitidine and cimetidine on the pharmacokinetics and pharmacodynamics of warfarin in man.

Stereochemical aspects of the potential interaction between the oral anticoagulant warfarin and the H2-antagonists, cimetidine and ranitidine, were investigated. A single 25 mg oral dose of racemic warfarin was administered on Day 4 of a randomised 9-day multiple dosing regimen of either cimetidine (800 mg o.d.) ranitidine (300 mg o.d.) or placebo. The degree of anticoagulation produced by warfarin was quantificated by the determination of both the prothrombin and Factor VII clotting times. Ranitidine had no effect on the pharmacodynamics of warfarin or the pharmacokinetics of the individual warfarin enantiomers. Cimetidine whilst producing no statistically significant change in the pharmacodynamics of warfarin or in the pharmacokinetics of the pharmacologically more potent (S) enantiomer, did produce a statistically significant decrease in the clearance of the (R) enantiomer, possibly due to metabolic inhibition of this species.

Adult↗
PubMed1987

Validation of assay methodology used in pharmacokinetic studies.

Statistical methods for validating assays used in pharmacokinetic studies are discussed. Methods for assessing linearity, variability, and sensitivity are derived. It is proposed that a calibration experiment, in which samples are replicated at three different concentrations, will provide the necessary information to validate an assay prior to commencement of a pharmacokinetic study and during its routine use. A two-stage weighted least squares regression is used to analyze the calibration data. High performance liquid chromatography calibration data are used to illustrate the principles and techniques involved.

Chromatography, High Pressure Liquid↗
PubMed1987

Enoxacin-warfarin interaction: pharmacokinetic and stereochemical aspects.

The interaction between the new quinoline-azaquinoline antibiotic enoxacin and the oral anticoagulant warfarin was investigated in six healthy male volunteers. Enoxacin was found not to affect the hypoprothrombinemic response produced by warfarin but did produce a decrease in the clearance of the less pharmacologically potent enantiomer of warfarin, (R)-warfarin. The decreased clearance of (R)-warfarin produced by concomitant enoxacin administration was found to be a consequence of inhibition by enoxacin of the (R)-6-hydroxywarfarin metabolic pathway.

Adult↗
PubMed1987

The effect of sulfinpyrazone on the disposition of pseudoracemic phenprocoumon in humans.

The effect of sulfinpyrazone on the pharmacokinetics and disposition of the enantiomers of pseudoracemic phenprocoumon was assessed by analyzing serial plasma, urine, and fecal samples for parent drug and metabolites by GC/MS. Essentially all of the administered dose could be accounted for either as parent drug, known metabolites, or their conjugates. Phenprocoumon and the 7-hydroxymetabolite represented the major materials recovered. All drug-related materials excreted into the urine were extensively conjugated. Sulfinpyrazone treatment did not affect the hypoprothrombinemia produced by phenprocoumon nor did it significantly alter the plasma elimination kinetics of the individual (R)- and (S)-enantiomers. However, an apparent increased free fraction of both enantiomers in plasma and inhibition of 7-hydroxylation of (S)-phenprocoumon were observed in the presence of sulfinpyrazone. The results of this study are contrasted with those of a previous study on the interaction between sulfinpyrazone and the structurally similar coumarin anticoagulant warfarin.

4-Hydroxycoumarins↗
PubMed1987

Pharmacokinetics of imipenem and cilastatin after their simultaneous administration to the elderly.

The pharmacokinetics of imipenem and cilastatin were studied in a group of six healthy elderly male volunteers following the combined intravenous administration of 500 mg imipenem and 500 mg cilastatin sodium as either single or multiple (6 hourly for 6 days) 20 min constant-rate infusions. The pharmacokinetics of both imipenem and cilastatin in the elderly were similar to those of young individuals with mild renal failure (Verpooten et al., 1984). There was no change in the pharmacokinetics of either species with time following multiple-dosing. Correlations existed between total clearance and the glomerular filtration-rate (51Cr-EDTA) for both imipenem and cilastatin.

Aged↗
PubMed1986

The warfarin-sulfinpyrazone interaction: stereochemical considerations.

To allow the simultaneous evaluation of the interaction between sulfinpyrazone and each enantiomer of racemic warfarin, pseudoracemic warfarin (1:1 12C-R(+) and 13C-S(-)warfarin) was given to six normal subjects both before and during oral sulfinpyrazone dosing. Serial blood and urine samples were analyzed for unchanged warfarin and its metabolic products by GC/MS. A mass balance of an oral dose of pseudoracemic warfarin, containing a tracer quantity of 14C-warfarin, was carried out in one of the subjects by monitoring 14C levels in urine and feces for 15 days. Concomitant sulfinpyrazone dosing markedly increased hypoprothrombinemia, decreased clearance of (S)-warfarin, and increased clearance of (R)-warfarin. Sulfinpyrazone also decreased the urinary excretion of warfarin-related products but increased their fecal excretion by an equivalent amount. Virtually all of the administered warfarin dose could be accounted for either as unchanged drug or known metabolites. Pharmacokinetic analysis of the data suggests the following: At least four distinct enzymes (two oxidases and two reductases) are involved in the metabolism of warfarin. Sulfinpyrazone increases the hypoprothrombinemia caused by warfarin primarily by inhibition of the cytochrome P-450-mediated oxidation of (S)-warfarin, the biologically more potent enantiomer. The increased clearance of (R)-warfarin results not from induction, but from its selective displacement from plasma protein binding sites.

Administration, Oral↗
PubMed1985

Metabolic fate of phenprocoumon in humans.

Samples of urine and feces were collected daily from a normal human volunteer who had received a dose of pseudoracemic phenprocoumon [an equimolar mixture of (R)-[12C]- and (S)-[2-13C]phenprocoumon] containing a tracer dose of 10 microCi of [14C]phenprocoumon and analyzed by TLC, HPLC, and GC-MS. After 25 days, 96% of the radiolabeled material was recovered (62.8% in urine and 33.3% in feces). By isotopic dilution and comparison to the Rf values, retention times, and mass fragmentograms of synthetic standards, the metabolites of the drug were identified as the 4'-, 6-, and 7-hydroxy analogues of phenprocoumon. Virtually all of the recovered radioactivity could be accounted for by the parent drug (approximately 40%) and the three metabolites (approximately 60%). The formation of both 4'-(8.1% of administered dose) and 7- (33.4% of administered dose) hydroxyphenprocoumon was highly stereoselective, giving S/R ratios of 2.86 and 1.69, respectively. The formation of 6- (15.5% of administered dose) hydroxyphenprocoumon showed little stereoselectivity (S/R ratio equal to 0.85). The urinary excretion pattern was also confirmed in four additional healthy male subjects who received a single oral dose of pseudoracemic phenprocoumon and whose urine was analyzed by GC-MS. All the drug-related materials (both hydroxylated metabolites and parent compound) that were excreted into the urine were extensively conjugated.

4-Hydroxycoumarins↗
PubMed1984

Liquid chromatographic determination of lipophilicity with application to a homologous series of barbiturates.

A graphical method for determining the lipophilicity of the members of a homologous series of barbituric acids, from a consideration of their reverse-phase HPLC retention data, is described. The HPLC parameter used as the index of lipophilicity, RQ, is shown not only to form excellent correlations with the more commonly employed indices of lipophilicity, Rm and log P, but also to have a predictive capability for those log P values that had not previously been determined experimentally.

Barbiturates↗
PubMed1983

Structure-pharmacokinetic relationships among the barbiturates in the rat.

The pharmacokinetics of a congeneric series of barbituric acids were determined after i.v. administration of individual barbiturates or multicomponent barbiturate mixtures to chronically cannulated male rats. The concentration of barbiturate in plasma and urine was determined using reversed-phase high-performance liquid chromatography. A biexponential equation adequately fitted the plasma-concentration time data. The volume of distribution remained relatively constant within the series. Binding to plasma proteins varied enormously, increasing with lipophilicity. Accordingly, the volume of distribution based on unbound drug also increased with lipophilicity, reflecting a corresponding greater tissue affinity. Total clearance formed a relatively complex nonlinear relationship with lipophilicity. Although the affinity of the barbiturates for erythrocytes increased with lipophilicity, the relationship between total blood clearance and lipophilicity offered no simplification. Renal clearance, the minor route of elimination for the majority of the homologs, decreased with increasing lipophilicity, due to increased tubular reabsorption, whereas nonrenal (hepatic) clearance produced a nonlinear relationship with lipophilicity similar in form to that of total clearance. The nonlinearity of the hepatic clearance within the series was explained by a hepatic blood flow limitation, for the highest homologs, and by the stereochemistry of position 5 on the barbituric acid ring, for the lowest homologs.

Animals↗