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Biomedical subjects

L N Sansom

Publications and source records attributed to L N Sansom.

At least 19 recordsLinked to original sources
PubMed1995

Human pharmacokinetics of tiludronate.

Tiludronate is a bisphosphonate evaluated extensively as an osteoregulator in the treatment of metabolic bone disorders. It is highly polar and has a low and variable oral absorption similar to its related compounds. An absolute bioavailability of approximately 6% has been reported with large inter- and intra-subject variability. The extent of absorption is increased at doses above 400 mg and may be reduced by a factor of 5 when tiludronate is administered with, or within 2 h after, food or dairy products. Approximately 90% of tiludronate is bound to serum albumin, and the binding is linear in the concentration range 1-10 mg/L. Preliminary in vitro studies using human hepatocytes failed to show any evidence of biotransformation of tiludronate. The elimination half-life in patients with normal renal function is approximately 40-60 h, but is significantly increased in subjects with severe renal impairment. The renal clearance (0.7 L/h) is independent of dose and suggests that glomerular filtration is the mechanism responsible for elimination. Approximately 50% of the absorbed dose is bound to bone and the rate of release of the drug from this site is limited by bone turnover. In vitro experiments indicate that tiludronate is not an enzyme inducer or inhibitor. Drug interaction studies with the nonsteroidal agents acetylsalicylic acid, indomethacin, and diclofenac indicate that only with indomethacin was there any change in the pharmacokinetic parameters, and that these changes were minimal and unlikely to be of clinical significance. Tiludronate does not influence the pharmacokinetics of digoxin at steady state. Tiludronate appears to exhibit similar pharmacokinetic behavior to other bisphosphonates with the exception that its absolute bioavailability is significantly higher than that previously reported for clodronate and pamidronate. The impact of its pharmacokinetic properties on clinical outcome has yet to be determined.

Administration, Oral↗
PubMed1995

Cyclophosphamide administered repeatedly to the male rat and as a single dose to the female rat. Its effects on hepatic and pulmonary P450 and associated enzymes.

1. Two different aspects of the effects of the cytotoxic agent cyclophosphamide (CP) on rat P450 and associated enzymes have been examined. 2. First, the effects of CP, administered as a single 200 mg/kg dose, on hepatic and pulmonary P450 and some associated enzymes in the female rat have been investigated. Second, the effects of repeat doses of CP (40 mg/kg on days 0-4 with killing on days 5, 8 and 11) to the male rat have been examined. 3. CP decreased the activity of the female rat hepatic enzymes 2A1, 2C6 and/or 2C12 and 2E1, NADPH-P450 oxidoreductase and 17 beta-oxidoreductase and the pulmonary enzyme 2B, 7 days after its administration. The decreases in the activity of the enzymes 2E1 and NADPH-P450 oxidoreductase were accompanied by a corresponding change in the amount of enzyme protein indicating that the alteration in expression of these enzymes occurred via changes in transcription and/or translation or protein degradation. 4. CP also impaired its own activation 7 days after its administration to the female rat. 5. The change in female enzyme profile was accompanied by a reduction in the hormones oestradiol, T4 and T3 7 days after CP administration. 6. Despite an apparent trend for an increase in activity on day 5, a decrease on day 8 and a subsequent increase on day 11, repeat doses of CP to the male rat generally did not alter the P450 isoforms 2A2, 2B1, 2C11, 2E1 and 3A2 or 17 beta-oxidoreductase, NADPH-P450 oxidoreductase and steroid 5 alpha-reductase. 7. Chronic administration of CP to the male rat significantly reduced erythromycin demethylase and NADPH-P450 oxidoreductase 8 days following commencement of dosing and significantly increased 2A2 11 days following commencement of dosing. There was also a statistically significant increase in pulmonary 2B 5 days following commencement of dosing. 8. Plasma testosterone and TSH were unchanged following repeated dosing with CP while T3 was significantly decreased on days 5, 8 and 11 and T4 was significantly decreased on day 8.

Animals↗
PubMed1993

Identification of two human brain aryl sulfotransferase cDNAs.

A 1,179 bp and a 1,424 bp full-length aryl sulfotransferase cDNAs were isolated from a human brain cDNA library. Their coding domains are 93% identical, each encoding a cytosolic protein of 295 amino acids. Their deduced amino acid sequences of these cDNAs are also 93% identical. The 1179 bp brain cDNA has an identical coding domain to a previously reported human liver aryl sulfotransferase cDNA but it has a different 5' noncoding sequence. Northern blot analysis using a probe specific for the 1,424 bp cDNA identified a 1500 bp band in mRNA of human liver, colon, kidney and lung. In a human hepatocellular carcinoma the same band plus an extra larger band was also recognised. An intron of the gene encoding the 1424 bp cDNA was also identified.

Amino Acid Sequence↗
PubMed1993

Molecular characterisation of a human aryl sulfotransferase cDNA.

A full-length aryl sulfotransferase cDNA was isolated from a human liver cDNA library. It was 1155 bp long containing a coding region of 885 basepairs encoding a cytosolic protein (M(r) 34178 Da) of 295 amino acids. This human cDNA shared 80% homology to the rat aryl sulfotransferase cDNA, 58% to the bovine and rat oestrogen sulfotransferase cDNAs, 53% to the rat hydroxysteroid sulfotransferase cDNA and 51% to the human liver dehydroepiandrosterone sulfotransferase cDNA over its whole 885 bp coding region. The deduced amino acid sequence of this human cDNA was 79% homologous to that of the rat aryl sulfotransferase cDNA and the putative common-substrate binding site motif GXXGXXK of the sulfotransferases has been conserved in this human amino acid sequence. At least two sizes of this human aryl sulfotransferase mRNA were detected in the human liver and lung.

Amino Acid Sequence↗
PubMed1993

cDNA expression studies of rat liver aryl sulphotransferase.

A cDNA encoding an isoenzyme of rat liver aryl sulphotransferase was isolated from a rat liver bacteriophage Lambda gt 11 library by the polymerase chain reaction technique. The resulting cDNA was functionally expressed in COS-7 cells and characterised by determining the sulphating capacity of the cells with a range of substrates. The COS-expressed enzyme catalysed the sulphation of both phenol and dopamine with Kms of the same order as those obtained for the high affinity isozyme in rat liver cytosol, while low activity was observed with tyrosine methyl ester. The common food additive vanillin was also a good substrate for sulphate conjugation. The sulphation of vanillin catalysed by the COS-expressed enzyme was consistent with a single enzyme system, in contrast, the kinetics of the reaction catalysed by cytosolic sulphotransferase indicated that vanillin was sulphated by more than one isozyme.

Animals↗
PubMed1992

Co-regulation of phenytoin and tolbutamide metabolism in humans.

1. The disposition of phenytoin and tolbutamide was compared in eighteen healthy young adults separately administered single therapeutic doses (sodium phenytoin 300 mg, tolbutamide 500 mg) of the two drugs. 2. Within the group, ratios of ranges of total and unbound areas under the plasma concentration-time curves were similar for both drugs. 3. There were significant (P < 0.001) correlations between total (r = 0.88) and unbound (r = 0.86) areas under the plasma phenytoin and tolbutamide concentration-time curves. 4. The results are consistent with the involvement of the same cytochrome P-450 isoenzyme(s) in the metabolism of tolbutamide and phenytoin.

Adult↗
PubMed1991

The inhibition of drug oxidation by anhydroerythromycin, an acid degradation product of erythromycin.

The inhibition of steroid 6 beta-hydroxylase activity by anhydroerythromycin, an acid breakdown product of erythromycin, has been studied and compared to the effects of erythromycin using liver microsomes from control and dexamethasone pretreated rats and human liver microsomes. Both anhydroerythromycin and erythromycin were found to be demethylated, thus both fulfil the prerequisites for possible metabolite-cytochrome P450 complex information. The formation of a metabolite-cytochrome P450 complex was demonstrated for anhydroerythromycin by preincubating NADPH fortified microsomes with anhydroerythromycin. This complex formation could be reversed by incubating the microsomes in 50 microM potassium ferricyanide. Anhydroerythromycin was a more potent inhibitor of androst-4-ene-3,17-dione (androstenedione) 6 beta-hydroxylation than erythromycin. Kinetic analysis shows that there are probably two cytochromes P450 involved in androstenedione 6 beta-hydroxylation in control rat microsomes both of which are inhibited by anhydroerythromycin. There are at least two forms of cytochrome P450 responsible for androstenedione 6 beta-hydroxylation in microsomes from dexamethasone pretreated rats but only the high affinity form is inhibited by anhydroerythromycin. "Atypical" kinetics were observed in human microsomes but inhibition of androstenedione 6 beta-hydroxylation was observed with 5 microM anhydroerythromycin at all androstenedione concentrations used. Inconsistencies have been observed in the literature with respect to clinical interactions observed with erythromycin. Since anhydroerythromycin appears to be a more potent inhibitor of androstenedione 6 beta-hydroxylation than erythromycin, we speculate that the variable blood levels of anhydroerythromycin found after dosing with erythromycin may explain these discrepancies.

Animals↗
PubMed1991

Relationship between phenytoin and tolbutamide hydroxylations in human liver microsomes.

1. The metabolic interaction of phenytoin and tolbutamide in human liver microsomes was investigated. 2. Phenytoin 4-hydroxylation (mean Km 29.6 microM, n = 3) was competitively inhibited by tolbutamide (mean Ki 106.2 microM, n = 3) and tolbutamide methylhydroxylation (mean Km 85.6 microM, n = 3) was competitively inhibited by phenytoin (mean Ki 22.6 microM, n = 3). 3. A significant correlation was obtained between phenytoin and tolbutamide hydroxylations in microsomes from 18 human livers (rs = 0.82, P less than 0.001). 4. Sulphaphenazole was a potent inhibitor of both phenytoin and tolbutamide hydroxylations with IC50 values of 0.4 microM and 0.6 microM, respectively. 5. Mephenytoin was a poor inhibitor of both phenytoin and tolbutamide hydroxylations with IC50 values greater than 400 microM for both reactions. 6. Anti-rabbit P450IIC3 IgG inhibited both phenytoin and tolbutamide hydroxylations in human liver microsomes by 62 and 68%, respectively. 7. These in vitro studies are consistent with phenytoin 4-hydroxylation and tolbutamide methylhydroxylation being catalysed by the same cytochrome P450 isozyme(s) in human liver microsomes.

Binding, Competitive↗
PubMed1991

Effect of racemic ibuprofen dose on the magnitude and duration of platelet cyclo-oxygenase inhibition: relationship between inhibition of thromboxane production and the plasma unbound concentration of S(+)-ibuprofen.

1. Four healthy male subjects received racemic ibuprofen (200, 400, 800 and 1200 mg), orally, on four occasions, 2 weeks apart, according to a four-way Latin-square design, in order to investigate the influence of increasing dose of ibuprofen on the magnitude and duration of its antiplatelet effect as well as on the relationship between such effect and drug concentration. 2. The antiplatelet effect of ibuprofen was assessed by measuring the inhibition of platelet thromboxane B2 (TXB2) generation during the controlled clotting of whole blood. The plasma unbound concentration of S(+)-ibuprofen, the enantiomer shown in an in vitro study to be responsible for the inhibitory effect of platelet TXB2 generation, was measured using an enantioselective method. 3. The maximum percentage inhibition of TXB2 generation increased significantly with dose from a mean +/- s.d. of 93.4 +/- 1.2% after the 200 mg dose to 98.8 +/- 0.3% after the 1200 mg dose, and there was an increase with dose in the duration of inhibition of TXB2 generation. The effect of ibuprofen on platelet TXB2 generation was transient and mirrored the time-course of unbound S(+)-ibuprofen in plasma; on all but one of the 16 occasions, serum TXB2 concentrations returned to at least within 10% of the pretreatment concentrations within 24 h of ibuprofen administration. 4. For each subject, the relationship between the percentage inhibition of TXB2 generation and the unbound concentration of S(+)-ibuprofen in plasma was modelled according to a sigmoidal Emax equation. The mean plasma unbound concentration of S(+)-ibuprofen required to inhibit platelet TXB2 generation by 50% (EC50) was 9.8 +/- 1.0 micrograms l-1.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Pharmacokinetic-pharmacodynamic modeling of the electroencephalographic effects of benzodiazepines. Correlation with receptor binding and anticonvulsant activity.

The relevance of EEG effect parameters as a measure of pharmacological effect intensity of benzodiazepines was evaluated. The concentration-EEG effect relationships of four benzodiazepine agonists, flunitrazepam, midazolam, oxazepam and clobazam, were quantified in individual rats and correlated with receptor affinity and anticonvulsant effect intensity of these compounds. Male Wistar-derived rats received a single i.v. dose of flunitrazepam (2.5 mg/kg), midazolam (5 mg/kg), oxazepam (10 mg/kg) and clobazam (20 mg/kg). Arterial blood samples were drawn frequently and EEG was monitored continuously until it had returned to preadministration levels. The concentrations of the benzodiazepines were determined by chromatographic means. Plasma protein binding was determined at 37 degrees C by ultrafiltration. The amplitudes in the 11.5 to 30 Hz frequency range, determined by aperiodic analysis, was used as EEG effect measure. Concentration-EEG effect relationships were derived by a pharmacokinetic-pharmacodynamic modeling procedure and characterized by the sigmoidal Emax model. The EC50 based on free drug concentrations (EC50,U, mean +/- S.E.) calculated for flunitrazepam (4.2 +/- 0.7 ng/ml) and midazolam (3.7 +/- 0.5 ng/ml) were similar and significantly less than the values for oxazepam (49 +/- 4 ng/ml) and clobazam (277 +/- 34 ng/ml) and illustrates the importance of using parameters referenced to unbound drug for comparative purposes. The maximal responses (Emax) for midazolam, oxazepam and clobazam were significantly less than for flunitrazepam suggesting that these three drugs may be regarded as partial agonists when compared to flunitrazepam. Receptor affinity was determined based on displacement of [3H] flumazenil in a washed brain homogenate at 37 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
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↗