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Biomedical subjects

M J Humphrey

Publications and source records attributed to M J Humphrey.

34 records · Page 2Linked to original sources
PubMed1981

Inhibition of thyroxine binding to serum proteins by fenclofenac and related compounds.

The anti-inflammatory drug fenclofenac lowers the serum concentrations of thyroxine (T4) and triidothyronine (T3) in subjects taking a regular dose of 600 mg twice daily. In eight male volunteers the concentration of T4 in serum was reduced to almost a third of the pre-treatment value while the concentration of T3 fell by about a half. The interaction of fenclofenac, and related compounds, while the thyroid hormone binding proteins of serum was studied in vitro by equilibrium dialysis with measurement of the concentrations of the free T4 and T3 in the dialysate by immunoassay. Fenclofenac, at a concentration of 100 mg/l (of the order achieved therapeutically), increased the concentrations of free T4 and by 131% and free T3 by 62%. The related compounds which increased the free hormone concentrations (although at higher concentrations than achieved during therapy) include diclofenac, monohydroxyfenclofenac and dihydroxyfenclofenac. A second in vitro method was used to study the interaction of these drugs with isolated thyroxine-binding globulin (TBG). An antiserum to TBG, coupled to Sephadex particles, was used to isolate TGB from other serum proteins. The effect of the different drugs on the binding of T4 by the immobilised TBG was then measured. These compounds competitively inhibit the binding of T4 by TBG, and for each an inhibitor constant (Ki) was determined.

Anti-Inflammatory Agents↗
PubMed1981

The effect of fenclofenac on thyroid function.

The non-steroidal anti-inflammatory agent fenclofenac competitively inhibits the binding of thyroxine(T4) and triiodothyronine (T3) by thyroxine-binding globulin(TBG). Eight male volunteers completed a 4-week study during which they took fenclofenac 600 mg twice daily. The concentration of fenclofenac in serum reached a plateau after 1 week of therapy after which the mean concentration(+/SEM) of the drug in serum was 78.6 o.2 mg/1. During the steady state period on treatment there were reductions of the mean serum concentrations of total T4 to 35% (P less than 0.001), total T3 to 55% (P less than 0.001), free T4 to 69% (P less than 0.001) and free T3 to 90% (NS) of the respective pretreatment values. There were also significant changes in the concentrations of thyrotropin and reverse T3 in serum. After starting treatment with fenclofenac serum concentrations of thyrotrophin fell to a nadir after 2-4 days at which time the mean concentration was 34% (P less than 0.01) of the pretreatment value, whilst reverse T3 values increased to a maximum of 136% (P less than 0.001) of the pretreatment values over 1-2 days. There was subsequently an increase of the thyrotrophin and a reduction in reverse T3 concentrations to normal by 2 weeks of pretreatment. Transient pituitary suppression was also suggested by the response to to thryotrophin-releasing hormone (TRH): 7 days after starting fenclofenac the mean thyrotrophin response was 62% (P less than 9.001) of the pretreatment value. After 4 weeks of fenclofenac the response of TRH had returned to normal. After discontinuing fenclofenac there was a transient increase in the mean concentration of thyrotrophin in serum, to 129% of the pretreatment value (P less than 0.001), with a subsequent return to normal. Four weeks after discontinuing fenclofenac the serum concentrations of thyroid hormones and thyrotrophin were normal.

Adult↗
PubMed1981

The systemic bioavailability of buprenorphine by various routes of administration.

The systemic bioavailability of buprenorphine has been studied in female rats following single doses (200 microgram kg-1) administered by one of six different routes. Relative to the 100% bioavailability from the intraarterial route the mean bioavailabilities were intravenous, 98%; intrarectal, 54%; intrahepatoportal, 49%; sublingual, 13%; and intraduodenal, 9.7%. Area under the curve analysis of buprenorphine concentrations in blood showed the relative fractions of drug extracted (first pass) by gut, liver and lung to be 0.80, 0.50 and 0.02 respectively, In situ absorption studies showed that the poor availability of intraduodenally administered buprenorphine is not due to slow or incomplete absorption.

Animals↗
PubMed1981

Biotransformation of tolmesoxide in animals and man.

1. The excretion and metabolism of tolmesoxide ((4,5-dimethoxy-2-methylphenyl)-methylsulphoxide) has been studied in rat, dog and man. In all species, absorption of oral doses of [14C]tolmesoxide was virtually complete and 78--99% of the 14C was excreted in the urine. 2. In bile-duct cannulated rats, excretion in bile and urine was 49% and 53% dose respectively. Metabolites of tolmesoxide in bile undergo enterohepatic circulation with final elimination by the kidneys. 3. Quantification and identification of metabolites in urine (0-24 h) were obtained by two-dimensional t.l.c. Tolmesoxide was extensively metabolized in all animal species. 4. The major routes of metabolism in rat, dog and man were oxidation to sulphones and O-demethylation followed by sulphate or glucuronide conjugation. Little or none of the urinary 14C was present as sulphide derivatives.

Adult↗
PubMed1981

Biliary excretion, metabolism and enterohepatic circulation of buprenorphine.

1. After intramuscular administration of [3H]buprenorphine to rats, dogs, rhesus monkeys and one human volunteer, most of the dosed radioactivity was excreted in the faeces, indicating biliary excretion and a possible enterohepatic circulation of the drug in these species. 2. After intravenous administration of [3H]buprenorphine (100 microgram/kg) to bile-duct cannulated rats, over 90% of the administered radioactivity was excreted in bile within 48 h after dosing. 3. The major drug-related component in rat bile was buprenorphine glucuronide. N-Dealkylated buprenorphine (again conjugated) was also present and a sex difference in the extent of N-dealkylation was apparent. 4. Intraduodenal infusion of rats with bile from rats dosed with [3H]buprenorphine produced a slow, although extensive, excretion of drug-related material in the bile of the recipient animals.

Animals↗
PubMed1980

Species differences in the metabolism and excretion of fenclofenac.

1. The excretion and metabolism of radiolabelled fenclofenac (2-(2,4-dichlorophenoxy)phenylacetic acid, Flenac) has been studied in five species. 2. In the rat, absorption of oral doses of fenclofenac was virtually complete and elimination occurred mainly by the bile and faeces. The guinea-pig excreted equal amounts of radioactivity in urine and faeces, while in rabbit, baboon and man renal excretion was the more important route. 3. In all species the majority of excreted radioactivity was present as fenclofenac ester glucuronide. Amino acid conjunction with fenclofenac was minimal in all species studied. 4. Mono- and di-hydroxylated metabolites have been detected in urine from guinea-pig, baboon and man. The major hydroxylated metabolite in baboon urine has been identified as 2-(2,4-dichlorophenoxy)-5'-hydroxyphenylacetic acid.

Absorption↗
PubMed1980

The metabolism of carfecillin in rat, dog and man.

1. The absorption of the phenol moiety of [phenol-14C]carfecillin following oral administration to rat, dog and man was extensive, since 95%, 73% and 99% of the administered radioactivity respectively was recovered in the urine. In contrast, less than half of the carbenicillin moiety of carfecillin was absorbed after oral administration, as judged by excretion studies using [carbenicillin-14C]carfecillin in intact and bile-duct cannulated animals. 2. The patterns of radiometabolites in the urines of rat, dog and man following single oral administration of [phenol-14C]carfecillin were determined by chromatography and radioassay. In two men, the majority of a dose was excreted as phenylsulphate (71%) and phenylglucuronide (16%) with the sulphate and glucuronic acid conjugates of quinol representing small amounts of the urinary radioactivity. Similar metabolic patterns were observed in the rat and dog following oral administration of either [14C]phenol or [phenol-14C]carfecillin, although some saturation of sulphate conjugation was apparent at the dose levels employed.

Adult↗
PubMed1980

The availability of carfecillin and its phenol moiety in rat and dog.

1. Studies have shown that hydrolysis of carfecillin to carbenicillin and phenol in vitro occurs in blood, liver and gut tissues of rat and dog. Extremely rapid hydrolysis was observed in the blood and liver of the rat. 2. Absorption studies in intestinally-perfused rats showed that following administration of either [14C]phenol or [phenol-14C]carfecillin, the half-life values of radioactivity in the intestinal lumen were 6 min and 47 min respectively. 3. Following oral administration of phenol to rats and dogs at 300 mg/kg and 40 mg/kg respectively, maximum plasma concn. of phenol were 26 microgram/ml. However, following oral administration of carfecillin to rats and dogs at dose levels of 3000 and 800 mg/kg respectively, no significant amounts of free phenol or intact carfecillin were detected (< 1 microgram/ml). The very low concentrations of phenol found after carfecillin administration and the concomitant absence of acute phenol toxicity is explained by the slow absorption of carfecillin and its slow hydrolysis to phenol in the gut lumen. 4. In the dog, phenol which enters the portal circulation as carfecillin appears to undergo significant 'first pass' metabolism by the liver, while no such effect was observed if free phenol was administered.

Animals↗
PubMed1976

Gastrointestinal absorption of carbenoxolone in the rat determined in vitro and in situ: deviations from the pH-partition hypothesis.

The absorption of [14C] carbenoxolone from everted rat ileum in vitro and from rat stomach and ileum in situ has been examined. The rate of its mucosal to serosal transfer in vitro increases as pH increases from 5 to 8 whereas the amount bound to ileum tissue decreases with increased pH; absorption closely parallels the drug's solubility. The uptake of carbenoxolone in situ is bi-exponential and the rate constants for the two processes, have been calculated. Absorption in situ, and biliary excretion, of the drug increases with increasing pH from 5.0 to 7.4. Tissue binding to the ileum in situ is not dependent on pH except below pH 5.0 when extensive tissue accumulation of carbenoxolone occurs because of its low solubility. Tissue binding to the stomach increases markedly with decrease of pH from 7.4 to 6.5 and at pH 6.5 is 80 times greater than binding to the intestine. The rate of absorption from the stomach, at pH 6.5-7.4, was much less than that from the intestine in situ. When allowance is made for the binding of carbenoxolone to the stomach, contrary to the pH-partition hypothesis, correlation is apparent between its absorption and the amount present in the ionized form.

Animals↗
PubMedDate not supplied

Bioanalytical data in decision making: discovery and development.

1. Bioanalysis is traditionally associated with the development phase of drugs; its use in discovery programmes is often ignored but can have a major impact. 2. Pharmacokinetic studies conducted in conjunction with pharmacology screening can provide additional information to that considered in conventional structure activity relationships. Such factors as half-life and bioavailability can be critical in designing improved drugs. 3. Analytical methods in discovery programmes may differ from those used in later development work: for instance bioassay allows a common assay system for a large number of project compounds. Moreover its use, when combined with conventional methods, such as h.p.l.c., allows active metabolites to be readily detected. 4. Bioanalytical data generated in discovery and pre-clinical programmes are a valuable guide to early clinical programmes. Plasma concentration-response data from these programmes can be compared with those obtained in man. Such comparisons are particularly valuable during the phase one-initial dose escalation study. To maximize this it is our practice to generate pharmacokinetic data between each dose increase.

Animals↗