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Biomedical subjects

T N Tozer

Publications and source records attributed to T N Tozer.

89 records · Page 5Linked to original sources
PubMedDate not supplied

First-pass elimination. Basic concepts and clinical consequences.

First-pass elimination takes place when a drug is metabolised between its site of administration and the site of sampling for measurement of drug concentration. Clinically, first-pass metabolism is important when the fraction of the dose administered that escapes metabolism is small and variable. The liver is usually assumed to be the major site of first-pass metabolism of a drug administered orally, but other potential sites are the gastrointestinal tract, blood, vascular endothelium, lungs, and the arm from which venous samples are taken. Bioavailability, defined as the ratio of the areas under the blood concentration-time curves, after extra- and intravascular drug administration (corrected for dosage if necessary), is often used as a measure of the extent of first-pass metabolism. When several sites of first-pass metabolism are in series, the bioavailability is the product of the fractions of drug entering the tissue that escape loss at each site. The extent of first-pass metabolism in the liver and intestinal wall depends on a number of physiological factors. The major factors are enzyme activity, plasma protein and blood cell binding, and gastrointestinal motility. Models that describe the dependence of bioavailability on changes in these physiological variables have been developed for drugs subject to first-pass metabolism only in the liver. Two that have been applied widely are the 'well-stirred' and 'parallel tube' models. Discrimination between the 2 models may be performed under linear conditions in which all pharmacokinetic parameters are independent of concentration and time. The predictions of the models are similar when bioavailability is large but differ dramatically when bioavailability is small. The 'parallel tube' model always predicts a much greater change in bioavailability than the 'well-stirred' model for a given change in drug-metabolising enzyme activity, blood flow, or fraction of drug unbound. Many clinically important drugs undergo considerable first-pass metabolism after an oral dose. Drugs in this category include alprenolol, amitriptyline, dihydroergotamine, 5-fluorouracil, hydralazine, isoprenaline (isoproterenol), lignocaine (lidocaine), lorcainide, pethidine (meperidine), mercaptopurine, metoprolol, morphine, neostigmine, nifedipine, pentazocine and propranolol. One major therapeutic implication of extensive first-pass metabolism is that much larger oral doses than intravenous doses are required to achieve equivalent plasma concentrations. For some drugs, extensive first-pass metabolism precludes their use as oral agents (e. g. lignocaine, naloxone and glyceryl trinitrate).(ABSTRACT TRUNCATED AT 400 WORDS)

Administration, Oral↗
PubMedDate not supplied

Nonenzymatic bioreduction in rat liver and kidney of nitroxyl spin labels, potential contrast agents in magnetic resonance imaging.

Paramagnetic nitroxyl spin labels have potential clinical utility as contrast agents in proton magnetic resonance imaging. Reduction of the nitroxyl moiety in vivo results in the formation of the diamagnetic hydroxylamine, which lacks contrast-enhancing activity. Bioreduction is therefore an important determinant of the imaging behavior of these agents. Both enzymatic and nonenzymatic reduction mechanisms have been suggested for nitroxyl spin labels. This study examines the nonenzymatic mechanisms in rat liver and kidney, mammalian tissues that demonstrate high reducing activity. Protein-free preparations, obtained by heat precipitation or ultrafiltration of rat liver and kidney homogenates, were used to test piperidine and pyrrolidine nitroxyl spin-label derivatives, for which imaging properties and bioreduction had previously been examined. For the piperidine derivative, the initial reduction rates in ultrafiltrates and supernatant fluids were 25-60% of those in whole liver and kidney homogenates. However, the pyrrolidine derivative was reduced at rates much slower than those in whole tissue homogenates. The reduction in whole tissue homogenates was NADPH-dependent, while reduction in ultrafiltrates was unaffected by the addition of NADPH. Preincubation of the ultrafiltrates and supernatant fluids with ascorbic acid oxidase caused almost complete inhibition of the reduction. The reduction rates of these nitroxyl derivatives were determined in ascorbic acid solution; second order rate constants were 0.45 +/- 0.04 and 0.0042 +/- 0.001 mM-1 min-1 for the piperidine and pyrrolidine derivatives, respectively. The concentrations of ascorbic acid in the supernatant fluids and ultrafiltrates of rat liver and kidney were then predicted from the observed reduction rates and found to be virtually identical with those from spectrophotometric determinations.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Biodisposition of theophylline. I. Genetic variation in inbred mice.

[8-14C]Theophylline was infused into mice with an osmotic minipump. Theophylline and its metabolites were separated from urine, blood, and feces by high-performance liquid chromatography and the radioactivity was determined by liquid-scintillation counting. The strains examined were SJL, DBA/2, C57BL/6, A/J, C3H/HeJ, AKR, SWR, and BALB/c. The theophylline clearance ranged from 479 +/- 30 ml/kg/hr in the A/J strain to 845 +/- 58 ml/kg/hr in the SJL strain. The total clearance in the A/J strain was signficantly different (p < 0.05) from that in the BALB/c, C57BL/6, and SJL strains. The metabolic pathway primarily responsible for this variation was the production of 1,3-dimethyluric acid.

Animals↗
PubMedDate not supplied

Biodisposition of theophylline. II. Effect of aromatic hydrocarbon treatment in mice.

The effect of polycyclic aromatic hydrocarbons on theophylline clearance was examined in six inbred mice strains. The DBA/2 and SJL strains were nonresponsive to this treatment, whereas C3H/HeJ, C57BL/6, BALB/c, and A/J strains were responsive. In the responsive strains, the total body clearance increased by a factor of 2.3 to 3.4, apparently due to a general induction of all metabolic pathways. The production of 1,3-dimethyluric acid was not increased in the C57BL/6 strain. The variation in induction among responsive strains appeared to be primarily associated with the increase in the oxidation to 1,3-dimethyluric acid.

Animals↗