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Biomedical subjects

W D Hooper

Publications and source records attributed to W D Hooper.

At least 73 records · Page 4Linked to original sources
PubMed1985

Disposition of beta-glucuronidase-resistant "glucuronides" of valproic acid after intrabiliary administration in the rat: intact absorption, fecal excretion and intestinal hydrolysis.

The major metabolite of valproic acid (VPA) is its beta-glucuronidase-susceptible glucuronide conjugate (VPA-G). At slightly alkaline pH such as in bile, VPA-G undergoes intramolecular rearrangement into at least six beta-glucuronidase-resistant isomers (VPA-G-R). The in vivo disposition of VPA-G-R was compared with those of VPA-G and VPA, each at 100 mg of VPA per kg, after intrabiliary administration to surgically prepared rats fasted during the experiments. Administered VPA was rapidly and completely absorbed into blood (peak 30 micrograms of VPA per ml at 0-2 hr). Administered VPA-G was predominantly hydrolyzed (beta-glucuronidase) in the intestine and liberated VPA absorbed into blood (peak 5 micrograms of VPA per ml at 6-9 hr). Administered VPA-G-R was disposed along at least three pathways: (1) part excretion, mainly unchanged, in feces (12% of dose); (2) part absorption (intact) from gut to blood and excretion in urine as VPA-G-R (3.6% of dose); and (3) part hydrolysis in the intestine (most likely by nonspecific esterases) with absorption of liberated VPA into blood (peak 2 micrograms of VPA per ml at 12-24 hr). The VPA/VPA-G/VPA-G-R composition of recovered dose in bile and urine was determined after all doses. In fed, nontraumatized rats given VPA-G-R p.o. at 100 mg of VPA per kg, 50% of the dose was recovered (mainly unchanged) in feces, a portion was absorbed intact into blood (2.5% of dose VPA-G-R excreted in urine) and the remainder hydrolyzed in the intestine with absorption of liberated VPA into blood.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1985

N-Alkyl barbiturates. A series of compounds for the study of metabolic structure-activity relationships.

Many therapeutic agents are metabolised along multiple pathways, but up to now there have been few investigations addressing the question of which chemical features of drugs govern the participation in, and quantitative significance of, different biotransformation pathways. To assess the influence of variations of the chemical structure upon metabolism, a series of novel barbiturate analogues has been synthesized. The N1-monoalkylated and N1,N2-dialkylated phenobarbitones and 2-desoxyphenobarbitones have been synthesized via condensation of ethylphenylmalonic acid derivatives with different N-alkylated ureas or thioureas, and/or by base-catalyzed N-alkylation of different barbituric acids.

Animals↗
PubMed1983

Chronic propranolol administration during pregnancy. Maternal pharmacokinetics.

The pharmacokinetics of propranolol (P) and its major metabolites, propranolol glucuronide (PGLUC), 4-hydroxypropranolol (4OHP), 4-hydroxypropranolol glucuronide (4OHPGLUC) and naphthoxylactic acid (NLA), (Walle et al. 1972) were determined, whenever possible, in the first, second and third trimesters of pregnancy in thirteen patients and also when these patients were at least three months post-partum. No correlations were found between the mean arterial blood pressure (post-therapy) or the fall in blood pressure as a result of the P therapy (p much greater than 0.05) and P dose, peak P plasma concentrations, peak 4-hydroxypropranolol (4OHP) plasma concentrations or peak (P plus 4OHP) plasma concentrations. However, a positive nonlinear relationship was found between the daily P dose (independent variable) and peak P plasma concentrations over the daily dose range 30-160 mg/day. The elimination half-lives of NLA for patients in the third trimester of pregnancy were significantly shorter (p = 0.072, df = 13) than those when the patients were at least three months post-partum. Also, the areas under the plasma level-time curves of NLA were significantly less (p less than 0.05, df = 13) for patients in the third trimester of pregnancy than when these patients were at least three months post-partum. The results of this study indicate that the pharmacokinetics of P, PGLUC, 4OHP and 4OHPGLUC are not significantly altered by pregnancy. However, the kinetics of NLA do appear to be altered. The formation of NLA by N-dealkylation of P and further oxidation, appears to be competitively inhibited by unidentified substances, perhaps endogenous steroids, especially in the third trimester when compared to at least three months post-partum.

Adult↗
PubMed1983

Metabolism of propranolol in the human maternal-placental-foetal unit.

Propranolol (P) and all of its major known metabolites were found in maternal plasma, cord plasma and neonatal plasma in 10 women at term, irrespective of the P doses administered and the time elapsed (up to 15 h) between administration of the last P dose and delivery. The ratios of cord plasma to simultaneous maternal plasma levels for propranolol and its major metabolites (mean +/- SD) were: propranolol 0.32 +/- 0.17, propranolol glucuronide 0.86 +/- 0.36, 4-hydroxypropranolol 1.4 +/- 1.0, 4-hydroxypropranolol glucuronide 0.71 +/- 0.45 and naphthoxylactic acid 3.0 +/- 1.6. P binding in cord plasma at delivery was 67.2 +/- 3.9% (mean +/- SD) which was significantly less ('t' = 13.4, df = 13, p less than 0.001) than the P binding in maternal plasma at delivery (87.5 +/- 1.6%, mean +/- SD). The plasma protein binding (mean +/- SD) of naphthoxylactic acid in cord plasma (98.6 +/- 0.2%) was significantly greater ('t' = 3.808, df = 4, p less than 0.02) than the naphthoxylactic acid binding in maternal plasma at delivery (97.6 +/- 0.4%). When the simultaneous concentrations of P and naphthoxylactic acid in maternal and cord plasma are compared in conjunction with protein binding and ionic effects, it would seem that metabolism of P does occur in the placental/foetal unit.

Blood Proteins↗
PubMed1983

Propranolol, propranolol glucuronide, and naphthoxylactic acid in breast milk and plasma.

High-performance liquid chromatographic assays for propranolol and its major metabolites in plasma and breast milk are described. The breast milk/whole plasma ratios of propranolol in three lactating women were in the range of 0.33 to 1.65. The half-life of elimination of propranolol from breast milk was 6.5 +/- 3.4 h (mean +/- SD), which was significantly longer (t = 1.844, df = 4, p less than 0.01) than the half-life of elimination of propranolol from plasma, which was 2.6 +/- 1.2 h (mean +/- SD). The half-life of elimination of the propranolol metabolite naphthoxylactic acid from breast milk was 4.2 +/- 0.9 h (mean +/- SD), which was not significantly different (t = 0.042, df = 4, p greater than 0.05) from the mean half-life of elimination from plasma, which was 4.2 +/- 1.2 h (mean +/- SD). The penetration of propranolol glucuronide into breast milk was slower and to a lesser extent than that of propranolol and naphthoxylactic acid. The maximum dose, calculated from the results presented in this paper, ingested as either propranolol or as propranolol glucuronide in breast milk by the neonate would be less than 0.1% of the maternal dose.

Female↗
PubMed1981

Single-dose pharmacokinetics of metoclopramide.

The time courses of plasma metoclopramide concentrations were followed in six subjects after oral and intravenous single dose administration. Plasma concentration-time data following i. v. administration in each subject were found to fit a two compartment model with a mean terminal half-life of 4.55 h +/- 0.80 h and a mean distribution half-time of 0.35 h +/- 0.09 h. Volumes of distribution were high (3.43 +/- 1.181 . kg-1), and clearances (0.53 +/- 0.191 . kg-1 h-1) approached liver plasma flow. This suggests that metoclopramide occurs at higher concentrations in tissues than in plasma, and that its clearance is probably limited by liver blood flow rather than liver metabolic capacity. The postabsorption decline in metoclopramide plasma levels after oral administration was also biexponential in each subject. The terminal half-life was 5.17 h +/- 0.98 h. Mean volume of distribution and mean clearance were similar to intravenous values (after adjustment for bioavailability). Oral absorption was rapid with peak plasma concentrations being reached at a mean time of 0.93 h. A mean bioavailability of 0.77 was calculated for the six subjects, and it was postulated that this incomplete availability is due to a first-pass effect. The inter-individual variation in the degree of "first-pass' was considerable (0.47--1.14).

Administration, Oral↗
PubMed1981

Pharmacokinetics and bioavailability of methylphenobarbital in man.

The pharmacokinetics and bioavailability of mephobarbital have been studied in 2 volunteers. Plasma levels of mephobarbital and phenobarbital were measured by gas chromatography-mass spectroscopy with selected ion monitoring. Urinary output of phenobarbital and the p-hydroxy derivatives of both mephobarbital and phenobarbital was measured by high pressure liquid chromatography. The time course of these plasma and urinary levels was monitored following single 800-mg oral and 200-mg intravenous doses in the 2 patients. The major conclusions of the study were that mephobarbital is reasonably well absorbed following oral dosing and that some 35% or so of the dose (by either route) is converted to the recently identified metabolite, p-hydroxymephobarbital.

Administration, Oral↗
PubMed1981

High performance liquid chromatographic assay of methylphenobarbital metabolites in urine.

A reversed-phase liquid chromatographic procedure was developed for simultaneous quantitation of three metabolites of the anticonvulsant methylphenobarbital in urine. These were p-hydroxyphenobarbital, phenobarbital, and p-hydroxymethylphenobarbital. Enzymatic hydrolysis was employed for liberation of the phenolic barbiturates from their glucuronide conjugates. Two internal standards were used at widely different concentrations, which conferred on the assay an accuracy over a wide concentration range. Concentration and instrument response (ultraviolet absorption at 215 nm) were linearly related over the concentration ranges of interest. The within-batch and between-day coefficients of variation were less than 4% in all cases. Recovery of all three analytes from the urine was nearly complete, and no substances that interfered with the assay were encountered in clinical specimens.

Chromatography, High Pressure Liquid↗
PubMed1980

Electron-capture gas chromatographic assay for metoclopramide in plasma.

An original electron-capture gas chromatographic assay has been developed for the quantiation of metoclopramide in human plasma. The method involves derivatization with heptafluorobutyryl imidazole after alkaline extraction, acid backwash, and a further alkaline extraction. Plasma levels of metoclopramide as low as 5 micrograms/l can be measured using 1 ml of plasma, and no interference from related substances or commonly prescribed drugs has been found. The percentage recovery of drug from plasma ranges from 88% to virtually 100%, and the between-run variation in the assay is 4.3%. The assay has been used for the study of metoclopramide pharmacokinetics in man following intravenous single-dose administration. The resultant plasma concentration vs. time curve was biexponential, with a terminal half-life of 5.0 h, and a distribution half-time of 0.3 h.

Acetylation↗
PubMed1978

Preliminary observations on the pharmacokinetics of methylphenobarbitone.

The pharmacokinetics of methylphenobarbitone and phenobarbitone were studied following the administration of methylphenobarbitone on a chronic basis in 77 patients, and after a single dose to each of 4 subjects who had received no other drugs and 4 subjects who had been pretreated with various anticonvulsants and other agents. At steady-state, plasma phenobarbitone concentrations correlated better with methylphenobarbitone dose than did plasma methylphenobarbitone concentrations. In this group the ratio of plasma phenobarbitone level to plasma methylphenobarbitone level was in the range of 7 to 10:1. In the single dose studies, mean values of elimination rate constant (0.0155h) and clearance (1.85L/h) for untreated subjects were different from those for the pretreated subjects (0.0375h and 5.10L/h), while the apparent volumes of distribution did not differ significantly between the two groups (120.3L vs 140.8L). The data are interpreted as most probably indicating induction of hepatic microsomal enzymes in the pretreated group.

Adult↗
PubMed1977

The pharmacokinetics of carbamazepine.

The time-courses of plasma carbamazepine concentrations were followed in six apparently healthy adult subjects who, at different times, took single oral drug doses of 200, 400, 500, 600, 700, 800 and 900 mg. There were some suggestions of impaired bioavailability of the drug when given in tablet form. The following values were obtained for various pharmacokinetic parameters: kabs = 0.176 +/- 0.209 h-1; k = 0.0203 +/- 0.0055 h-1; T1/2 = 37.5 +/- 13.1 h; VD = 0.825 +/- 0.1041 . KG-1; Clearance = 0.0163 +/- 0.0061 1 . kg-1. The elimination rate constant showed a statistically significant increase with increasing drug dose. This may help explain the clinical observation that the rate of rise of steady state plasma carbamazepine concentrations tends to decrease with dose increase in patients taking carbamazepine alone.

Adult↗
PubMed1977

Factors influencing plasma phenobarbitone levels in epileptic patients.

1 Various statistical techniques were used to study the effects of age, sex and concurrent therapy with other anticonvulsants on the relation between plasma phenobarbitone levels and doses of (i) phenobarbtione, (ii) methylphenobarbitone or (iii) primidone, in epileptic patients. 2 Methylphenobarbitone and primidone are converted to phenobarbitone in the body. The mean doses of phenobarbitone, methylphenobarbitone and primidone which produced the same plasma phenobarbitone level (15 microgram/ml) were, respectively, 1.75,2.75 and 7.75 mg kg-1 day-1. 3 For both phenobarbitone and methylphenobarbitone dose requirement to achieve a given plasma phenobarbitone level fell progressively with age. Sex influenced the relation between plasma phenobarbitone level and phenobarbitone or methylphenobarbitone dose. Interactions were detected between primidone and both phenytoin and carbamazepine. 4 In individual patients, within the limits of dosage studied, the relation between plasma phenobarbitone level and drug dose was not rectilinear if phenobarbitone itself was taken, but was rectilinear if methylphenobarbitone was taken.

Adolescent↗
PubMed1976

Plasma drug concentrations in therapeutics.

The literature describing drugs assay in plasma and its value for optimal therapy for individual patients is expanding rapidly. The present review seeks to clarify the rationale underlying the assay of plasma concentrations of drugs, and it attempts to define principles for judging the likely value of assaying a particular drug. Examples are given of drugs which are being usefully measured in clinical practice. The most commonly used assay techniques are briefly described, and their principal advantages and limitations are indicated.

Biological Assay↗
PubMed1976

The effects of phenobarbitone dose on plasma phenobarbitone levels in epileptic patients.

The relation between plasma phenobarbitone level and phenobarbitone dose was studied in 121 patients. The relation changed with age, the dosage requirement (on a day weight basis) tending to fall as patients grew older. Males under 5 years had a higher dosage requirement than females of the same age, but otherwise sex did not affect the relationship, nor did the concurrent intake of the anticonvulsants phenytoin, carbamazepine or sulthiame. In the individual, plasma phenobarbitone levels tended to increase out of proportion of dosage increases. These findings can provide a basis for prescribing appropriate phenobarbitone doses in epileptics.

Adolescent↗