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Biomedical subjects

W D Hooper

Publications and source records attributed to W D Hooper.

At least 55 records · Page 3Linked to original sources
PubMed1990

Enantioselective binding of mephobarbital to plasma proteins.

The enantioselective protein binding of mephobarbital (MPB) was investigated in human plasma and human serum albumin solutions by equilibrium dialysis. A small but statistically significant difference was observed in the in vitro plasma protein binding of the enantiomers; (S)-MPB was approximately 59% bound and (R)-MPB approximately 67% bound. The binding to albumin [(S)-MPB: approximately 29% bound, and (R)-MPB: approximately 41% bound] was less than to plasma proteins but showed somewhat greater enantioselectivity, suggesting that albumin binding is a major source of the enantioselectivity in plasma. The effects of MPB concentration, of varying enantiomeric concentration ratio, and of phenobarbital on the enantioselective binding of MPB were studied. The effect of age was also investigated by measuring the binding in plasma from 8 young (18-25 yr) and 8 elderly (greater than 60 yr) male subjects who took single doses of MPB. The results were in close agreement with the in vitro binding data, and the binding of both enantiomers was marginally but significantly lower in the young compared with the elderly subjects. These differences in binding were consistent with previously observed pharmacokinetic differences between the two subject groups.

Adult↗
PubMed1990

The influence of age and gender on the stereoselective metabolism and pharmacokinetics of mephobarbital in humans.

In this clinical investigation, four groups of subjects (eight young women and eight young men [age range, 18 to 25 years], and eight elderly women and eight elderly men [greater than 60 years of age]) received single oral doses (400 mg) of racemic mephobarbital. The apparent total body clearance of R-mephobarbital was much greater and the elimination half-life was much shorter in the young men compared with the other three groups. This enantiomer displayed an age-dependent gender effect and a gender-dependent age effect in its metabolism. The apparent total body clearance of the S-enantiomer was much lower than that of the R-enantiomer in all subjects and did not differ between subject groups, although the elimination half-life was slightly but significantly shorter in young males. A consequence of these enantiomeric differences was an apparently enhanced stereoselectivity in the metabolism of mephobarbital in young men. These substantial influences of age and gender on the stereoselective disposition of mephobarbital are consistent with recent findings concerning the expression and regulation of cytochrome P450 enzymes.

Adolescent↗
PubMed1990

Effect of food on absorption of lomefloxacin.

Twelve subjects participated in an open-label, single-dose, balanced three-way crossover study in which the absorptions of lomefloxacin were compared following (i) an overnight fast, (ii) a carbohydrate meal, and (iii) a high-fat meal. The time to peak concentration of lomefloxacin was delayed, but peak concentration in plasma and amount of drug absorbed were unchanged following both meals.

4-Quinolones↗
PubMed1990

Cytochrome P450IIIA enzymes in rat liver microsomes: involvement in C3-hydroxylation of diazepam and nordazepam but not N-dealkylation of diazepam and temazepam.

Microsomes prepared from livers of male and female rats of nine inbred and outbred strains and of male Sprague-Dawley rats pretreated with monooxygenase-inducing agents were used to study N-dealkylation of diazepam and temazepam and C3-hydroxylation of diazepam and nordazepam. Both C3-hydroxylation reactions were more rapid in male than in female liver preparations, but this gender-dependent pattern was not seen with the N-dealkylation reactions. These results indicate the lack of identity of the monooxygenases responsible for the two kinds of reaction and suggest that male-specific enzyme(s) are responsible for the C3-hydroxylations. Induction studies were undertaken to further define these enzymes. To do this, liver microsomes prepared from male Sprague-Dawley rats pretreated with a variety of agents known to have different monooxygenase induction effects were used. With triacetyloleandomycin, dexamethasone, and phenobarbital pretreatment, the specific activities of the C3-hydroxylation reactions were selectively elevated over corresponding control values. These particular xenobiotics are known to enhance the abundance of cytochrome P450IIIA family enzymes, and our results strongly suggest the involvement of these enzymes in the benzodiazepine B ring monooxygenations. Formation of temazepam was also shown to be inhibited by triacetyloleandomycin. This effect was demonstrated to be equal in both saline-treated and dexamethasone-treated male Sprague-Dawley rat liver microsomes, with the antibiotic present either with diazepam throughout the entire incubation period or initially with NADPH in a preincubation mix for 15 min, following which C3-hydroxylation was initiated by the addition of diazepam. These results confirm the uniformity of the involvement of cytochrome P450IIIA family enzymes in diazepam C3-hydroxylation in untreated and inducer-treated rat liver microsomes. Recent studies with human and rabbit liver microsomal preparations have shown that orthologues of these enzymes also catalyze an equivalent hydroxylation in the B ring of midazolam. These findings, considered with the present results showing that the adjacent methyl N-substituent (absent in nordazepam but present in diazepam) did not affect the selectivity of these enzymes for the C3-hydroxylation reaction, suggest that neither steric nor electronic factors markedly influence catalysis of this monooxygenation by these enzymes.

Animals↗
PubMed1989

First dose and steady-state pharmacokinetics of oxcarbazepine and its 10-hydroxy metabolite.

The pharmacokinetics of oxcarbazepine (a new anticonvulsant which is a congener of carbamazepine) and of its 10-hydroxy metabolite were studied at the outset of therapy in 8 adult epileptics comedicated with other anticonvulsants. The pharmacokinetic study was repeated under steady-state conditions after 3 months of drug intake in 6 of these subjects. The plasma elimination half-life of oxcarbazepine appeared to lie in the range 1.0-2.5 h, and that of its 10-hydroxy metabolite averaged 8.4 h. The apparent oral clearance of the parent drug (averaging 2.51.kg-1.h-1) was high enough to suggest substantial presystemic elimination. The oral clearance fell after 3 months of drug intake, but the half-lives of the drug and metabolite showed no statistically significant change over this time. Steady-state plasma levels of both drug and metabolite were linearly related to drug dose, metabolite levels averaging 9 times those of the parent substance.

Adult↗
PubMed1989

Urinary excretion of valproate and some metabolites in chronically treated patients.

Urinary excretion of the antiepileptic agent valproic acid (VPA) and major metabolites from its glucuronidation, beta-oxidation, and omega- and omega 1-hydroxylation pathways were studied under steady state conditions in 24 epileptic patients. Some 55 +/- 18% (SD) of the daily dose was recovered in urine, 33 +/- 14% in the form of VPA-glucuronide, 15 +/- 8% as beta-oxidation products, and 4 +/- 2% and 2 +/- 1% as products of the omega- and omega 1-hydroxylation pathways, respectively. Only 1 +/- 2% of the dose was excreted unchanged. The proportion metabolized by direct glucuronidation tended to increase with dose at the expense of the oxidative pathways, particularly beta-oxidation. However, the wide variation in the patterns of urinary metabolite excretion precludes use of routinely collected urinary excretion data as a basis for detecting any but severe noncomplicance with VPA therapy or abnormalities of VPA metabolism.

Adolescent↗
PubMed1989

The effect of pregnancy in humans on the pharmacokinetics of stable isotope labelled phenytoin.

1. To investigate the mechanism of the fall in steady-state plasma phenytoin concentration relative to drug dose that occurs during pregnancy, single dose pharmacokinetic studies with stable isotope labelled phenytoin were carried out at different stages of pregnancy, and 2 to 4 months post-natally, in five epileptic women receiving regular oral therapy with the drug. 2. Steady-state apparent plasma clearances of phenytoin (dose/steady-state concentration) correlated closely with simultaneous plasma clearances of the intravenous stable-isotope drug (measured as dose/AUC) suggesting that the patients were complaint with therapy when their phenytoin dosage requirement increased during the pregnancy, and that the oral drug was fully bioavailable. 3. In retrospect, two of the five subjects were probably studied too early post-natally for phenytoin elimination kinetics to have returned to non-pregnant values. Despite this, (i) the mean +/- s.d. t 1/2 for phenytoin was statistically significantly shorter in pregnancy than post-natally (31 +/- 14 vs 39 +/- 28 h), (ii) the mean +/- s.d. whole plasma clearance was also statistically significant greater (0.025 +/- 0.012 vs 0.021 +/- 0.013 kg-1 h-1) and (iii) the mean +/- s.d. Vmax for phenytoin elimination was statistically significantly greater in pregnancy (1170 +/- 600 mg day-1) than post-natally (780 +/- 470 mg day-1). Although the mean +/- s.d. apparent Km was higher in pregnancy (18.2 +/- 8.4 mg l-1, expressed in terms of whole plasma drug concentrations, compared with 10.2 +/- 7.4 mg l-1 post-natally), the difference was not statistically significant. However, if the apparent Km value was expressed in terms of plasma water phenytoin concentrations the difference (pregnant 2.50 +/- 0.85 mg l-1: post-natally 1.16 +/- 0.65 mg l-1) was statistically significant. 4. Human pregnancy appears to result in an increased capacity to eliminate phenytoin.

Adult↗
PubMed1988

Disposition of phenytoin and phenobarbitone in the isolated perfused human placenta.

1. The disposition of the anti-epileptic agents phenytoin (PHT) and phenobarbitone (PB) was investigated in lobules of term human placentae perfused using separate maternal and fetal circulations for 6 h periods. 2. No evidence for metabolism of PHT or PB to their p-hydroxylated or other derivatives was found either in perfused lobules or by incubation with placental microsomes. 3. Both PHT and PB were readily transferred across the placenta after administration to either the maternal or fetal perfusates. 4. PHT, unlike PB, showed considerable accumulation in placental tissue.

Biotransformation↗
PubMed1988

Markers of physical integrity and metabolic viability of the perfused human placental lobule.

1. Peripheral lobules of term placentae obtained from healthy females at Caesarian section were perfused using separate maternal and fetal circulations for 6 h periods under either oxygenated or anoxic conditions. 2. Markers of physical integrity during setting-up and initial perfusion were establishment of dual perfusion within 25 min of placental delivery, pressure in the fetal capillary network less than 40 mmHg, leakage of perfusate from fetal to maternal compartments less than or equal to 2 ml/h, and overlap of maternal with fetal perfusion as indicated visually by appropriate blanching and verified by a fetal artery to vein oxygen gradient of greater than or equal to 90 mmHg. 3. Post-perfusion markers of metabolic viability were most reliably indicated by glucose consumption (oxygenated 7.8 +/- 1.5, anoxic 17.7 +/- 1.2 mmol/kg per h), lactate production (oxygenated 8.5 +/- 1.4, anoxic 33.9 +/- 2.5 mmol/kg per h) and human placental lactogen production (oxygenated 41.2 +/- 9.8, anoxic 12.2 +/- 3.4 mg/kg per h).

Female↗
PubMed1988

Further clinical and pharmacokinetic observations on the new anticonvulsant, oxcarbazepine.

Continuing experience with oxcarbazepine has shown that the drug tends to be less sedative than carbamazepine and at least as potent as an anticonvulsant but much more likely to cause hyponatraemia. The behaviour of the clearance of oxcarbazepine over a period of 3 months raises the possibility that the drug may not be as active an inducer of drug metabolism as is carbamazepine.

Adult↗
PubMed1987

Intermittent carbamazepine intoxication possibly related to altered absorption characteristics of the drug.

In Australia intermittent carbamazepine intoxication that occurs around the expected time of the peak post-dose plasma drug concentrations has been seen more frequently in recent years than in the past. Reworking of pharmacokinetic data from earlier studies of the drug suggests that, between 1977 and 1980, there was a change in the absorption profile of carbamazepine in the most widely used oral Australian preparation of the drug. The drug's absorption rate increased and its peak plasma levels occurred earlier. The reason for this altered absorption profile cannot now be traced, but it seems a possible explanation for the clinical problem that has emerged subsequently in a number of patients.

Absorption↗
PubMed1987

Identification and synthesis of O-methylcatechol metabolites of phenobarbital and some N-alkyl derivatives.

5-Ethyl-5-(4-hydroxy-3-methoxyphenyl) barbituric acid was identified as a new, minor metabolite of phenobarbital in man. The identity of this O-methylcatechol metabolite was confirmed by an unequivocal chemical synthesis, and by GC-MS studies. Mephobarbital and the 1,3-dimethyl, 1-ethyl, and 1,3-diethyl analogues of phenobarbital yielded the corresponding N-alkylated O-methylcatechol metabolites, all of which were confirmed by synthesis. The N-alkyl barbiturates each gave additionally at least one O-methylcatechol metabolite in which N-dealkylation had occurred. These metabolites accounted for approximately 1-5% of the orally administered dose in man.

Catechols↗
PubMed1987

Oxcarbazepine: preliminary clinical and pharmacokinetic studies on a new anticonvulsant.

Oxcarbazepine is a new anticonvulsant, currently undergoing clinical trials. Its spectrum of antiepileptic action, and its chemical structure, resemble those of carbamazepine, though the 2 drugs have no pharmacologically active metabolites in common. In a study of 7 adults with poorly controlled partial epilepsy, progressive substitution of oxcarbazepine for carbamazepine left seizure control unaltered in 4 and improved in 3, whilst 5 became more alert and one was rendered ataxic. Three subjects became hyponatraemic. There were no other adverse effects. Plasma levels of the drug and its pharmacologically active 10-hydroxy derivative were measured sequentially over 4 days after a single drug dose at the outset of therapy in 5 subjects. Calculated pharmacokinetic parameter values for the drug, assuming complete oral bioavailability, were: absorption lag time 2.07 +/- 1.61 h: absorption rate constant 8.328 +/- 8.941 h-1: apparent volume of distribution 3.937 +/- 2.222 L kg-1: oral clearance 2.898 +/- 1.439 L kg-1: elimination rate constant 0.609 +/- 0.261 h-1 (half-life 1.26 +/- 0.37 h), while the metabolite had a formation rate constant of 0.593 +/- 0.233 h-1, and an elimination rate constant of 0.082 +/- 0.014 h-1 (half-life 8.74 +/- 1.79 h). Even with a single dose, peak plasma metabolite levels were substantially higher than those of the parent drug. Oxcarbazepine appears to be a promising alternative to carbamazepine as an anticonvulsant, although in view of its rapid elimination it probably serves mainly as a prodrug for its 10-hydroxy metabolite.

Adult↗
PubMed1986

"Radiochemically pure [1-14C]valproic acid"--a mixture of labeled structural isomers.

Ongoing studies of the disposition of valproic acid (VPA) and its glucuronide conjugate required the radiolabeled drug for greater sensitivity and tracing of oxidation metabolites. [1-14C]VPA hereinafter called LABEL (radiochemical purity greater than 98% as determined by paper and thin layer chromatography) was purchased from Amersham International, U.K. Quantitative analysis of VPA and VPA-glucuronide in bile and urine samples from rats given VPA and tracer LABEL by our standard gas chromatographic assay showed gross discrepancies with the results obtained by liquid scintillation counting of the same extracts. Examination of the purity of LABEL was therefore undertaken. Equilibration of LABEL between various organic-aqueous solvent pairs was identical to that of authentic VPA. However, gas chromatographic-mass spectrometric analysis of the trimethylsilyl derivative of LABEL revealed it to be a mixture of labeled 2-methylheptanoic acid (approximately 60%), 2-ethylhexanoic acid (approximately 30%), and 2-propylpentanoic acid (i.e., VPA, 5-10%). The origin of the isomers of VPA in LABEL was logically traced to the synthetic procedure--coupling of the Grignard reagent of (an isomeric mixture of 2-, 3-, and 4-) chloroheptane(s) with [14C]carbon dioxide. This result highlights the inadequacy of the quality control procedures used and reinforces the necessity for caution in accepting the quoted purity of radiolabeled drugs.

Carbon Radioisotopes↗
PubMed1985

Simultaneous plasma carbamazepine and carbamazepine-epoxide concentrations in pharmacokinetic and bioavailability studies.

A comparative bioavailability study of carbamazepine (CBZ) in tablets and a syrup preparation was carried out in six volunteers, using a crossover design. Plasma and saliva samples were collected at appropriate times, and the plasma specimens were analyzed by high performance liquid chromatography for concentrations of CBZ and its epoxide metabolite (CBZ-EP). Analysis of the data showed that the preparations were equally bioavailable, although absorption was faster from the syrup and gave higher maximum plasma levels of CBZ. In other respects the preparations were pharmacokinetically equivalent. Analysis of simultaneous plasma CBZ and CBZ-EP concentration-time data by iterative curve fitting to a one-compartment linear model permitted the calculation of elimination kinetic parameters of the CBZ-EP; the mean elimination half-life was 6.9 +/- 2.7 h. Failure of the salivary CBZ concentrations soon after drug intake to correlate with simultaneous plasma CBZ levels rendered the salivary data useless for bioavailability comparison, but prompted a further study of salivary CBZ levels.

Adult↗
PubMed1985

Fallacious results from measuring salivary carbamazepine concentrations.

During a carbamazepine (CBZ) relative bioavailability study involving tablets and a syrup preparation, salivary drug concentrations appeared disproportionately high relative to simultaneous plasma drug concentrations in the first 2-3 h after oral drug intake. This raised the suspicion of contamination of saliva by retention of drug in the mouth. In a separate study CBZ was retained in the mouth in tablet form (whole or crushed) or in syrup, for only 5 s before being spat out, and the mouth was carefully rinsed. Despite this, measurable salivary concentrations, sufficient to cause substantial error if extrapolated to simultaneous plasma drug concentrations, were present for at least 2 h after drug administration. CBZ in these studies disappeared from saliva with an apparent mean half-life of 21.0 +/- 4.8 min. This experience suggests that, in therapeutic drug monitoring, salivary CBZ concentrations for at least 2 h after dosage may lead to invalid conclusions about simultaneous plasma CBZ concentrations.

Administration, Oral↗
PubMed1985

Extent of urinary excretion of p-hydroxyphenytoin in healthy subjects given phenytoin.

Urinary excretion of p-hydroxyphenytoin and its glucuronide conjugate was measured in eight healthy young adults in a comparative bioavailability study of oral sodium phenytoin (approximately 5 mg/kg/dose). Among these subjects the percentage of the phenytoin dose converted to p-hydroxyphenytoin and appearing in urine was relatively similar (mean 79%, range 67-88%). The great majority of the p-hydroxyphenytoin appeared in urine as conjugates; only 1.4-3.4% of the excreted p-hydroxyphenytoin was in the form of unconjugated metabolite. The proportion of a single phenytoin dose excreted in urine as p-hydroxyphenytoin or its conjugate increased from the first dose (mean +/- SD) 74.9 +/- 4.6% to the second dose, given 2 weeks later 79.3 +/- 4.6% (p less than 0.05). This finding suggests that autoinduction of phenytoin metabolism may occur after relatively brief exposure to the drug.

Adult↗