Biomedical subjects
Publications and source records attributed to J B Houston.
The systemic availability of phenol following rectal administration to rats has been compared to intraduodenal and intravenous administration via the hepatic portal and jugular veins. Phenol blood concentration-time curves after the rectal route of dosing indicate that first pass conjugation by the intestinal mucosa and liver is drastically reduced when compared to the other routes of administration.
The effect of four inhibitors of cytochrome P-450-mediated drug oxidations (SKF 525A, cimetidine, metyrapone and alpha-naphthoflavone) on the urinary metabolite pattern and 14CO2 exhalation rate (CER)-time profile following [N-methyl-14C]antipyrine administration has been investigated. The CER-time profiles indicated that inhibition of antipyrine metabolism was in the rank order SKF 525A greater than cimetidine greater than metyrapone greater than ANF. The urinary metabolite patterns showed selectively in action towards particular pathways, 3-hydroxylation being primarily decreased by SKF 525A and cimetidine, and N-demethylation by ANF. The results provide further evidence for involvement of multiple forms of cytochrome P-450 in antipyrine metabolism.
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Blood concentrations of promethazine and promethazine sulphoxide have been measured following oral and intravenous administration of promethazine to seven healthy male volunteers. Promethazine disposition is characterised by a large volume of distribution (1970 1) and a high blood clearance (1.141 min-1). Less than 1% of the dose is excreted unchanged in the urine, therefore total body clearance is essentially metabolic clearance. In accord with this high clearance the oral availability of promethazine is only 25%. The absorption of promethazine from the gastrointestinal tract exceeds 80% in most subjects. Minimal metabolism by the gastrointestinal mucosa is implicated. Promethazine sulphoxide pharmacokinetics are consistent with a pronounced first pass effect. Although the area under the curve for this metabolite is not route dependent, there is a marked alteration in the shape of the metabolite curve when oral and intravenous data are compared. Evidence is presented to support the hypothesis that S-oxidation of promethazine is predominantly an hepatic event. The conclusions of previous investigators with regard to the role of the gut mucosa in S-oxidation of phenothiazines is critically assessed.
Promethazine blood concentration-time curves have been determined in 7 rabbits following intravenous, oral and hepatic portal vein administration of promethazine. This phenothiazine has a large volume of distribution and a high metabolic clearance resulting in low blood concentrations particularly when the oral route is used. Analysis of the areas under the blood concentration-time curves indicates that hepatic first-pass metabolism is the major determinant of promethazine's low oral availability. Absorption from the gastrointestinal tract is essentially complete in most rabbits and the contribution of metabolism by the intestinal mucosa is minimal. The present findings are compared with the literature on other phenothiazines.
The absorption of prednisolone in patients with Crohn's disease was investigated. Seven patients with Crohn's disease and eight normal control subjects were given a tracer dose of tritiated prednisolone with 20 mg cold prednisolone by mouth. On a separate occasion they were given an intravenous injection of radiolabelled prednisolone. After oral ingestion only 53.4 +/- 11.7% of labelled material was excreted in the urine of Crohn's patients compared with 82.5 +/- 3.6% in the normal subjects. The oral/intravenous availability ratio was 0.61 +/- 0.14 in Crohn's patients and 0.89 +/- 0.07 in the normal group. Areas under plasma concentration-time curves were lower in patients than normal subjects and the oral/intravenous ratios were 0.6 +/- 0.2 and 0.86 +/- 0.09 respectively. Faecal excretion of radioactivity after oral ingestion was greater in Crohn's patients (19.3 +/- 2.5%, n = 3) than in normal subjects (7 +/- 2.8%, n = 4). The range for each type of measurement was much wider in the patient group than in the normal subjects. These data suggest that patients with Crohn's disease do not absorb prednisolone normally and that absorption varies between patients.
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1 A comparison of total sulphapyridine saliva concentrations resulting from administration of sulphapyridine and sulphasalazine at equimolar doses has been carried out. It is concluded that the extent of azo reduction of sulphasalazine to release sulphapyridine is complete in healthy volunteers. 2 An ampicillin course of treatment alters the azo reduction of sulphasalazine. The extent of cleavage is reduced by one third on average. There is no change in the rate of absorption of the release sulphapyridine. 3 An ampicillin course of treatment does not alter the disposition of sulphapyridine. The changes noted in acetyl conjugate plasma concentrations are entirely consistent with reduced availability of sulphapyridine.
1 Aminopyrine breath tests make use of the commercially available (N-dimethyl-[14C])-aminopyrine. A pharmacokinetic model has been proposed to relate 14CO2 exhalation rates (CER) to the demethylation of ([14C]-methyl)-aminopyrine (AP) and -monomethylaminoantipyrine (MAP). 2 computer simulations based on the model show that the shape of the CER-time profile is largely dependent on the ratio of the MAP to AP elimination rate constants. If this ratio equals 0.5 then the CERs decline in the monoexponential fashion. Ratios less than 0.5 result in concave biexponential curves whereas ratios greater than 0.5 result in convex curves. When demethylation is not complete for both compounds the transfer from biexponential to monoexponential behaviour will only occur at ratios greater than 0.5. 3 The resolution of concave biexponential CER-time profiles to give accurate estimates of AP and MAP elimination rate constants can only be achieved when the length of the experiment is adequate. The commonly employed 2 microCi tracer dose of aminopyrine is insufficient to monitor CER over the necessary time period to detect the proposed biexponential decline.
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1. An h.p.l.c. method for the simultaneous determination of naphthol, naphthyl glucuronide and naphthyl sulphate in urine is described. This procedure is based on the selective formation of an ion pair between the sulphate conjugate and tetrabutyl lammonium, which allows its resolution from the glucuronide on a reverse phase column. 2. The h.p.l.c. method is sed to assess the selective enzyme hydrolysis method which is frequently employed in drug conjugate assays. Results suggest that the use of sulphatase and beta-glucuronidase may give data which are quantitatively and qualitatively erroneous.
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Plasma concentration-time profiles for amidopyrine and its primary desmethyl metabolite have been determined in control rats and in rats pretreated with phenobarbitone. The kinetics of both compounds indicate enhanced clearance following pretreatment. Metabolite excretion in urine, bile and breath support the plasma data. It would appear that pheno barbitone pretreatment results in quantitative but not qualitative changes in the metabolism of amidopyrine in rat.
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