Search PubMed⌕ Search

Biomedical subjects

L N Sansom

Publications and source records attributed to L N Sansom.

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

Phenytoin 4-hydroxylation by rabbit liver P450IIC3 and identification of orthologs in human liver microsomes.

The ability of rabbit liver microsomes to 4-hydroxylate phenytoin to 5-(4-hydroxyphenyl)-5-phenylhydantoin was studied. No significant difference was observed between the capacity of control and rifampicin, phenobarbital, acetone, 2,3,7,8-tetrachlorodibenzo-p-dioxin and phenytoin induced rabbit liver microsomes to 4-hydroxylate phenytoin. In reconstitution experiments using six purified rabbit cytochromes P450 isozymes, only P450IIC3 was capable of 4-hydroxylating phenytoin whereas P450IA1, P450IA2, P450IIB4, P450IIIA6, and P450IVB1 were inactive. Further, anti-P450IIC3 IgG completely inhibited phenytoin 4-hydroxylase activity in rabbit liver microsomes. The above data suggest a major role for the constitutive isozyme P450IIC3 in phenytoin 4-hydroxylase activity in rabbit liver. In human liver microsomes P450IIC3 IgG inhibited phenytoin 4-hydroxylase activity by 66%, suggesting that an ortholog to rabbit P450IIC3 is in part responsible for this activity in man.

Animals↗
PubMed1990

Bioavailability of a new sustained-release theophylline capsule in fasted and non-fasted healthy subjects: single and multiple dosing studies.

Eighteen healthy, non-smoking, adult volunteers participated in single and multiple dose three-way crossover studies to evaluate a sustained-release, pellet-filled capsule of theophylline, Austyn. The effect of food on the bioavailability of the sustained-release capsule was investigated by administering 300 mg single doses of Austyn, with a high-fat meal and without food and a divided 300 mg dose of the reference product Elixophyllin elixir, given after fasting. Plasma theophylline concentrations were measured by fluorescence polarization immunoassay (FPIA) which had been validated against HPLC. The single dose study data showed that there were no significant differences (n = 18, ANOVA, p greater than 0.05) between the three regimens with respect to AUC0-infinity values (mg h l-1), (mean +/- SD); Elixophyllin fasting = 97.1 +/- 33.7, Austyn with food = 90.9 +/- 31.3, Austyn fasting = 91.2 +/- 33.8. Similarly, multiple dosing with rapid-release Nuelin tablets, Austyn capsules, and sustained-release Theo-Dur tablets demonstrated that there were no significant differences between regimens with respect to AUC0-24h, AUC0-12h, and AUC12-24h values calculated from the steady-state concentrations (5th day, 24 h sampling). However, the percentage fluctuation at steady-state over the total blood sampling period was significantly less for treatment with the sustained-release capsule. Austyn, compared with the sustained-release tablet, Theo-Dur (Austyn = 36.7 +/- 13.7 per cent, Theo-Dur = 53.1 +/- 14.1 per cent). The results of the single and multiple dose studies indicate that Austyn capsules demonstrate complete bioavailability, and good controlled release characteristics not influenced by concomitant intake of a high-fat meal and with no evidence of dose dumping.

Adult↗
PubMed1990

Plasma and cerebrospinal fluid concentration of temazepam following oral drug administration.

Thirteen male patients were administered 20 mg of temazepam orally 1 to 2 h prior to undergoing spinal anaesthesia for a urological procedure. Samples of blood and CSF were drawn just before insertion of the spinal and the concentration of drug estimated in these two media. The results obtained indicated that a highly significant correlation existed between the unbound concentration of temazepam in plasma and the concentration of drug present in CSF. Temazepam appeared to be an effective light pre-medicant in all of the subjects studied.

Administration, Oral↗
PubMed1989

Stereoselective plasma protein binding of ibuprofen enantiomers.

We have developed a novel and reproducible method for determining the plasma protein binding of the two ibuprofen enantiomers in the presence of each other. The method involves the use of radiolabelled racemic ibuprofen, equilibrium dialysis, derivatization of the enantiomers to diastereomeric amides, high-performance liquid chromatography, and radiochemical analysis. We have determined the plasma protein binding of R(-)- and S(+)-ibuprofen in 6 healthy male volunteers after the oral administration of 800 mg racemic ibuprofen. The mean time-averaged percentage unbound of the R(-)-enantiomer, 0.419 was significantly less than that of the S(+)-enantiomer, 0.643, consistent with stereoselective plasma protein binding. The percentage unbound of each ibuprofen enantiomer was concentration-dependent over the therapeutic concentration range and was influenced by the presence of its optical antipode.

Adult↗
PubMed1989

Lack of effect of cimetidine on the pharmacokinetics of R(-)- and S(+)-ibuprofen.

1. To investigate the effect of cimetidine on the pharmacokinetics of R(-)- and S(+)-ibuprofen, six healthy male volunteers received orally 800 mg racemic ibuprofen both in the drug-free state (control phase, C) and on the second day of a 3 day course of oral cimetidine, 1 g daily (treatment phase, T). The two phases (14 days apart) were randomised in a balanced cross-over manner. 2. The plasma concentrations of R(-)- and S(+)-ibuprofen were measured by high-performance liquid chromatography (h.p.l.c.). The protein binding of the enantiomers was assessed in a selection of plasma samples from each volunteer. Following alkaline hydrolysis of glucuronide conjugates, the urinary recoveries of ibuprofen and its major metabolites were measured by h.p.l.c. 3. There was no difference (P greater than 0.05, two-tailed Student's t-test; data expressed as mean +/- s.d.) between C and T phases in the total area under the plasma concentration-time curve of R(-)-ibuprofen (C 4514 +/- 1063 mg 1(-1) min vs T 4665 +/- 1435 mg 1(-1) min) and S(+)-ibuprofen (C 6460 +/- 1063 mg 1(-1) min vs T 6886 +/- 1207 mg 1(-1) min). Similarly, for each enantiomer, there was no difference between the two phases in the terminal half-life, the maximum plasma concentration or the time of its occurrence. 4. Cimetidine treatment had no effect (P greater than 0.05) on the time-averaged percent unbound in plasma of R(-)-ibuprofen (C 0.419 +/- 0.051% vs T 0.435 +/- 0.060%) and S(+)-ibuprofen (C 0.643 +/- 0.093% vs T 0.633 +/- 0.053%). (ABSTRACT TRUNCATED AT 250 WORDS)

Absorption↗
PubMed1988

Pharmacokinetics of a new sublingual formulation of temazepam.

The pharmacokinetics of a new 10 mg sublingual tablet formulation of temazepam and those of a currently marketed 10 mg oral capsule formulation were evaluated in a group of ten healthy volunteers. No significant differences were observed between the two formulations with respect to any of the pharmacokinetic parameters assessed. Lethargy and somnolence were reported on both capsule and tablet by several subjects at a time which corresponded with the maximum concentration of drug in plasma. The data indicate that the sublingual tablet and orally administered capsule have a similar pharmacokinetic and pharmacodynamic profile.

Administration, Oral↗
PubMed1988

Lack of effect of erythromycin on the pharmacokinetics of single oral doses of phenytoin.

The effect of erythromycin on the pharmacokinetics of phenytoin was studied in eight healthy volunteers using a balanced randomised cross-over design. Volunteers received a single oral dose of 400 mg of phenytoin sodium during each phase. During the treatment phase, the phenytoin sodium dose was administered 4.5 days after the commencement of a 7 day course of erythromycin base (250 mg every 6 h). There was no significant difference between the control and treatment phases (P greater than 0.05) with respect to the area under the plasma phenytoin concentration-time curve, the fraction of phenytoin unbound in plasma, the area under the unbound phenytoin concentration-time curve, the elimination half-life of phenytoin or the fraction of the dose excreted in urine as free and conjugated hydroxyphenylphenylhydantoin. This single dose study indicated that the intrinsic clearance of unbound phenytoin was unaffected by the concurrent administration of erythromycin.

Administration, Oral↗
PubMed1988

Stereoselective drug disposition: potential for misinterpretation of drug disposition data.

1. Although it is well recognised that the enantiomers of a chiral drug may possess different pharmacokinetic and pharmacodynamic properties, many studies dealing with chiral drugs which are administered as their racemates rely on non-stereoselective analytical techniques. 2. We present a theoretical analysis to illustrate the potential which exists for misinterpretation of drug disposition and plasma drug concentration-effect data generated for a racemic drug using a non-stereoselective assay. 3. It was shown that the use of such an analytical method can lead to the collection of data which may be both quantitatively and qualitatively inaccurate with respect to the individual enantiomers. For example, the clearance of the unresolved drug may indicate concentration- and time-dependence even though this pharmacokinetic process is concentration- and time-independent for each of the enantiomers. 4. The problems discussed emphasise the need to consider stereoselectivity in clinical pharmacological studies involving racemic drugs.

Humans↗
PubMed1987

The pharmacokinetics of ketoconazole after chronic administration in adults.

We have studied the pharmacokinetics of the anti-mycotic ketoconazole in seven patients who took it for 1-6 months at a dose of 200 mg daily. The mean elimination half-life of the drug was 3.3 h, and although the ketoconazole was given only once daily, a satisfactory clinical response was obtained in all seven individuals. Only a small fraction of the absorbed drug (mean 0.22%) was excreted unchanged in the urine, suggesting almost complete metabolism. Our results support the concept that anti-mycotic activity in the tissues continues after the plasma drug concentration has fallen below a critical level. Our results also support the concept of a change in pharmacokinetics with chronic dosing.

Adult↗
PubMed1985

Moxalactam kinetics during continuous ambulatory peritoneal dialysis after intraperitoneal administration.

Moxalactam kinetics during continuous ambulatory peritoneal dialysis (CAPD) was followed in eight patients after a single intraperitoneal dose of 1 g. Approximately 60% of the dose was absorbed after a dwell time of 4 h. Dialysis solutions were exchanged at 4-h intervals with an overnight dwell of 8 h. The mean (+/- standard deviation) elimination half-life was 13.2 +/- 2.9 h, and the mean apparent volume of distribution was 0.22 +/- 0.08 liters/kg. Mean total clearance was 11.5 +/- 2.4 ml/min, with a mean dialysis clearance of 2.3 +/- 0.5 ml/min. The maximum concentration in plasma ranged from 24.5 to 54.1 micrograms/ml. Moxalactam concentrations in the peritoneal dialysis fluid were above 80 micrograms/ml during the first exchange and above 2 micrograms/ml for a further three exchanges. A suggested intraperitoneal dose regimen for patients undergoing CAPD is 1 g initially, followed by 15 to 25% of the recommended dose for normal patients given at the same time intervals, or 30 to 50% of the recommended dose at twice the usual intervals. Moxalactam is suggested for initial treatment of peritonitis in CAPD patients who do not have ready access to the antibiotic of choice.

Adult↗
PubMed1984

Aspirin metabolites causing misinterpretation of paracetamol results.

The inadequacy of single, simple arithmetic corrections for salicylate interference in the widely employed Glynn and Kendal technique for plasma paracetamol assay is highlighted by reference to an actual case of combined salicylate/paracetamol intoxication in an infant. Attention is drawn for the first time to the not insubstantial contribution to such interference made by even the minor metabolites of salicylate. The conclusion is reached that is necessary, particularly in the assessment of paracetamol toxicity, to determine the presence of salicylate, and when present, to employ a specific method for the estimation of paracetamol.

Acetaminophen↗
PubMed1981

A comparison of the pharmacokinetics of theophylline in asthmatic children in the acute episode and in remission.

The pharmacokinetics of theophylline following a single intravenous dose of aminophylline were determined in 8 asthmatic patients in each of the acute, the recovery and the remission phase. The overall results for mean plasma theophylline clearance (78.6 +/- 33.3 ml/kg/h), plasma theophylline half-life (4.14 +/- 1.36 h) and apparent volume of distribution (0.41 +/- 0.066 l/kg) are in accordance with previously published values. There was no general statistically significant difference in any of the pharmacokinetic parameters when results from the acute and remission phases were compared. However, certain patients showed reductions in plasma theophylline clearance in the acute phase of the illness such that a dosage regimen standardised during remission may cause toxicity if continued in the acute episode. It is suggested that monitoring the plasma theophylline levels is desirable in all patients in the acute episode.

Acute Disease↗
PubMed1981

Interaction between phenytoin, 5-(p-hydroxyphenyl)-5-phenylhydantoin and valproate in the rat.

The effect of valproate on the pharmacokinetics of phenytoin after a single i.v. injection is described in this study. Valproate is shown to significantly increase the total clearance, i.e., 23.8 to 30.4 ml . min-1 . kg-1 and volume of distribution, i.e., 0.92 to 1.25 liter . kg-1. No significant change was shown for the half-life of phenytoin. The pharmacokinetic parameters calculated for unbound phenytoin showed no significant differences between those rats infused with phenytoin or phenytoin-valproate. Significantly higher concentrations of 5-(p-Hydroxyphenyl)-5-phenylhydantoin (HPPH) were observed in those rats given an i.v. injection of phenytoin-valproate. In vitro studies with rat liver microsomes demonstrated that valproate inhibits the metabolism of HPPH to its glucuronide. This was further exemplified when significant differences were observed in the clearance and volume of distribution of HPPH in rats given an i.v. injection of HPPH or HPPH plus valproate. The results of this study demonstrate that in the rat valproate displaces phenytoin from serum proteins and that this interaction accounts for the increased volume of distribution and clearance of total phenytoin when valproate is coadministered. However, this displacement had no effect on the pharmacokinetics of free (unbound) phenytoin. Valproate is shown to be an inhibitor of the glucuronidation of HPPH which may explain the significantly increased concentrations of HPPH observed in the rats administered phenytoin-valproate.

Animals↗
PubMed1980

Interaction between phenytoin and valproate.

Displacement of phenytoin from plasma proteins by valproate causes a reduction in total serum phenytoin levels. However, no adjustment of phenytoin dosage is warranted, unless clinically indicated, since the free phenytoin levels remain unchanged.

Blood Proteins↗
PubMed1979

Comparative bioavailability of a microcrystalline theophylline tablet and uncoated aminophylline tablets.

The bioavailability of a rapidly dissolving tablet of theophylline and three brands of standard aminophylline tablets was estimated in a four way cross-over study involving 8 healthy adult volunteers. The relative extent of bioavailability as assessed by the measurement of the total area under the plasma concentration time curves showed no difference between the products (P greater than 0.05). Computed estimates of the rate of drug absorption were similar for all 4 products tested. The results indicate that the rapidly dissolving tablet offers no advantage in respect to rate and extent of absorption over conventional aminophylline tablets.

Aminophylline↗
PubMed1975

Bioavailability of phenytoin from various pharmaceutical preparations in children.

In children, the blood level of phenytoin was found to be significantly higher when 100 mg capsules rather than 100 mg tablets were administered. When, on the other hand, 30 mg capsules and tablets were compared; the situation was reversed; tablets produced significantly higher blood levels of phenytoin than did the capsules. The significance and possible explantation of these findings are discussed.

Adolescent↗