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D McKillop

Publications and source records attributed to D McKillop.

30 records · Page 2Linked to original sources
PubMed1991

Different inhibition and induction profiles of hepatic drug metabolism in rats and dogs by two structurally related pyridyl diazinone cardiotonic agents.

ICI 153,110 and ICI 170,777, two pyridyl diazinone cardiotonic agents, produced a different profile of effects on hepatic microsomal mixed function oxidase enzymes following multiple oral dosing to rats and dogs; these differences may be related to the molecular dimensions of the two molecules. ICI 153,110 significantly increased levels of total P450, ethoxycoumarin O-deethylase and ethoxyresorufin O-deethylase in rat microsomes, indicating an induction profile (P448) similar to that of beta-naphthoflavone. This was supported by gel electrophoresis (SDS-PAGE) of microsomal proteins; a similar type of induction was observed in dog microsomes. In contrast, ICI 170,777 produced no changes indicating enzyme induction in either rat or dog. Instead, ICI 170,777 appeared to inhibit specifically the activity of aldrin epoxidase in the rat. Inhibitory activity was also indicated in the rat by prolongation of pentobarbitone sleeping time following single oral doses of either ICI 153,110 or ICI 170,777. The time-course of this effect appeared to correlate more closely with the profile of circulating metabolites, although both parent compounds were found to produce type II spectral changes on interaction with control rat microsomes. The molecular dimensions (area/depth2) of the compounds supported the finding that only ICI 153,110 should interact with or induce P448 isozymes.

Animals↗
PubMed1990

The metabolic disposition of an orally active pyridyl thiadiazinone cardiotonic agent (MPTD) in rat and baboon.

1. Oral absorption and bioavailability of the orally active cardiotonic agent, (6RS)-6-methyl-5-(pyrid-4-yl)-3H,6H-1,3,4-[6-14C]thiadiaz in-2-one (MPTD) (5 mg/kg), in rat and baboon were high. Peak blood concentrations of MPTD and total radioactivity were reached by 1.5-4 h when MPTD accounted for 60-70% of total radioactivity. In both species, elimination of MPTD from blood was rapid (t 1/2 = 3-4 h), although total nonspecific radioactivity was eliminated more slowly. 2. Radioactivity was rapidly eliminated by both species mainly into urine. In rat, about 3% dose was collected as 14CO2 and 2% remained in the carcass after 4 days. Recovery from baboon was incomplete (78-86%). 3. Examination of urine indicated extensive metabolism of MPTD showing a marked species difference. In baboon, MPTD was metabolized largely by glucuronidation at the pyridyl nitrogen to yield a quaternary ammonium conjugate and only about 1% of the dose was excreted unchanged. In rat, the major urinary component was unchanged MPTD and no glucuronide conjugate was found. Both species formed the pyridine N-oxide of MPTD as well as a number of unidentified minor components. 4. Distribution of radioactivity in rat was rapid and extensive. In general, elimination from tissues was also rapid, although radioactivity was eliminated much more slowly from the nasal and bronchiolar epithelium and from the preputial gland.

Administration, Oral↗
PubMed1988

The metabolism of propranolol (ICI 45,520, Inderal) and xamoterol (ICI 118,587, Corwin) by isolated rat hepatocytes: in vivo-in vitro correlations.

1. The metabolism of two compounds which undergo predominantly Phase I (propranolol) and Phase II (xamoterol) metabolism in vivo has been studied in isolated rat hepatocytes. 2. Propranolol was rapidly metabolized by rat hepatocytes to a number of metabolites which correlated well with those observed in vivo. The effect of saturable metabolism on the in vitro clearance of propranolol at high substrate concentrations was very similar to the changes observed in vivo. 3. Xamoterol was metabolized by rat hepatocytes to produce mainly xamoterol glucuronide, with the sulphate conjugate of xamoterol representing a minor component. The low rate of formation of xamoterol sulphate is probably due to the low affinity of xamoterol for the sulphotransferase enzyme, since supplementation with inorganic sulphate did not significantly alter the rate of sulphation; the sulphotransferase system of these hepatocytes was however shown to be active in the metabolism of phenol. 4. The correlations observed between the known routes of metabolism of propranolol and xamoterol in vivo and those observed in isolated hepatocytes support the utility of isolated hepatocytes as a predictive model of metabolic events in vivo.

Animals↗
PubMed1985

Effects of phenobarbitone and beta-naphthoflavone on hepatic microsomal drug metabolising enzymes of the male beagle dog.

Hepatic microsomes, prepared from male beagle dogs treated with phenobarbitone or beta-naphthoflavone, were compared with microsomes from control dogs and from control, phenobarbitone and beta-naphthoflavone treated rats with respect to various microsomal enzyme activities and for protein profiles generated on sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE). The concentration of total cytochrome P-450 (0.46 nmoles/mg protein) and aldrin epoxidase (0.44 nmoles/mg/min) was lower in control dogs than in the rat, although ethoxycoumarin O-deethylase (ECOD-1.03 nmoles/mg/min) was 2 times and ethoxyresorufin O-deethylase (EROD-0.10 nmoles/mg/min) 5 times higher in the control dogs examined. Possibly as a result of this difference, beta-naphthoflavone induced ECOD 10-fold and EROD 100-fold in the rat, while these enzymes were only increased 3-fold and 5-fold respectively in the two beta-naphthoflavone-treated dogs. Consistent with this, control dog microsomes were found to contain a 58,000 mol. wt protein band that was not present in the SDS-PAGE of control rat microsomes but which was induced in both species by beta-naphthoflavone. Although not identical, the effects of each inducer on the protein profiles were similar in both species. beta-Naphthoflavone produced a marked increase in relative liver weight and, in contrast to published work in the rat, also increased NADPH-cytochrome c reductase levels in the dog. In general, the effects of phenobarbitone were qualitatively and quantitatively similar in both the dog and the rat.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1976

The metabolism and binding of catecholamines by the hepatic microsomal mixed-function oxidase of the rat.

Noradrenaline and adrenaline were metabolized by an NADPH- and oxygen-dependent process located within the hepatic microsomal fraction of the rat. Metabolism was inhibited by CO and compound SKF 525A, but not by pargyline, an inhibitor of monoamine oxidase, or by 3,4-dimethoxy-5-hydroxybenzoic acid, an inhibitor of catechol O-methyltransferase. It is concluded that the enzyme system responsible for the metabolism of the catecholamines was the microsomal mixed-function oxidase. The Km for noradrenaline was 2.4 mM and for adrenaline 1.0 mM, and V 15.6 and 3.6 nmol/min per mg of microsomal protein respectively. Both catecholamines bound to the microsomal fraction, producing a type II spectral change, with a Ks for noradrenaline of 0.9 mM and for adrenaline of 1.0 mM, and showed other characteristics of type II compounds by inhibited the reduction of cytochrome P-450 by NADPH and exhibiting an enhanced metabolism in the presence of acetone. The major product of catecholamine metabolism was an as yet unidentified alkali-labile compound, which did not correspond to any of the recognized catecholamine metabolites.

Animals↗
PubMedDate not supplied

In vitro metabolism of gefitinib in human liver microsomes.

The in vitro metabolism of gefitinib was investigated by incubating [14C]-gefitinib, as well as M537194, M387783 and M523595 (the main metabolites of gefitinib observed in man), at a concentration of 100 microM with human liver microsomes (4 mg ml(-1)) for 120 min. These relatively high substrate and microsomal protein concentrations were used in an effort to generate sufficient quantities of metabolites for identification. HPLC with ultraviolet light, radiochemical and mass spectral analysis, together with the availability of authentic standards, enabled quantification and structural identification of a large number of metabolites. Although 16 metabolites were identified, metabolism was restricted to three regions of the molecule. The major pathway involved morpholine ring-opening and step-wise removal of the morpholine ring and propoxy side chain. O-demethylation of the quinazoline methoxy group was a quantitatively less important pathway, in contrast to the clinical situation, where O-desmethyl gefitinib (M523595) is the predominant plasma metabolite. The third metabolic route, oxidative defluorination, was only a minor route of metabolism. Some metabolites were formed by a combination of these processes, but no metabolism was observed in other parts of the molecule. Incubation of gefitinib produced ten identified metabolites, but the use of the three main in vivo metabolites as additional substrates enabled a more comprehensive metabolic pathway to be constructed and this has been valuable in supporting the more limited data available from the human in vivo study.

Cells, Cultured↗