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D McKillop

Publications and source records attributed to D McKillop.

At least 19 recordsLinked to original sources
PubMed1999

Determination of the human cytochrome P450 isoforms involved in the metabolism of zolmitriptan.

1. Zolmitriptan was extensively metabolized by freshly isolated human hepatocytes to a number of components including the three main metabolites observed in vivo (N-desmethyl-zolmitriptan, zolmitriptan N-oxide and the indole acetic acid derivative). In contrast, metabolism of zolmitriptan by human hepatic microsomes was extremely limited with only small amounts of the N-desmethyl and indole ethyl alcohol metabolites being produced. 2. Furafylline, a selective inhibitor of CYP1A2, almost completely abolished the hepatocellular metabolism of zolmitriptan and markedly inhibited formation of the N-desmethyl metabolite in microsomes. Chemical inhibitors, selective against other major human cytochrome P450 (CYP2C9, 2C19, 2D6 and 3A4), had no obvious effects. In addition, expressed human CYP1A2 was the only cytochrome P450 to form the N-desmethyl metabolite. 3. N-desmethyl-zolmitriptan was extensively metabolized by both human hepatocytes and microsomes. The indole acetic acid and ethyl alcohol derivatives were the major metabolites formed by hepatocytes, whereas only the indole ethyl alcohol derivative was produced by microsomes. Metabolism of N-desmethyl-zolmitriptan was not inhibited by cytochrome P450-selective chemical inhibitors nor was it observed following incubation with expressed human cytochrome P450. Clorgyline, a selective inhibitor of monoamine oxidase A (MAO-A), markedly inhibited the microsomal formation of the indole ethyl alcohol derivative. 4. Primary metabolism of zolmitriptan is dependent mainly on CYP1A2, whereas MAO-A is responsible for further metabolism of N-desmethyl-zolmitriptan, the active metabolite. Since the in vivo clearance of zolmitriptan is primarily dependent on metabolism, interactions with drugs that induce or inhibit CYP1A2 or MAO-A may be anticipated.

Cimetidine↗
PubMed1999

Preclinical and in vitro assessment of the potential of D0870, an antifungal agent, for producing clinical drug interactions.

1. D0870, an azole antifungal agent, produced dose-related increases in total cytochrome P450 and aldrin epoxidase when administered as 14 daily oral doses (0, 0.5, 2.5 and 12.5 mg/kg/day) to the male rat. Administered as single doses, D0870 increased pentobarbitone-sleeping time in a dose-related manner. 2. In human hepatic microsomal incubations, D0870 produced pronounced inhibition of CYP2C9 (tolbutamide hydroxylase) and, to a lesser degree, CYP3A4 (testosterone 6beta-hydroxylase), but had more limited effects on CYP1A2, 2C19 and 2D6 activity. In comparison with ketoconazole, itraconazole and fluconazole, D0870 was the most potent inhibitor of CYP2C9 activity. It is predicted that D0870 may inhibit the in vivo clearance of CYP2C9 substrates by approximately 58%, thereby increasing their steady-state concentrations by 2.4 times, which would be of clinical significance for some compounds. 3. During incubation of [14C]-D0870 with cultured human hepatocytes for up to 72 h, two discrete metabolites (A and B) were formed. Formation of metabolite A was abolished by both quinidine and ketoconazole and is probably CYP3A4-mediated, whereas generation of metabolite B did not appear to be dependent on cytochrome P450. 4. D0870 has potential to produce both induction and inhibition of cytochrome P450 enzymes in man.

Animals↗
PubMed1998

Effects of propofol on human hepatic microsomal cytochrome P450 activities.

1. The potential of propofol to inhibit the activity of major human cytochrome P450 enzymes has been examined in vitro using human liver microsomes. Propofol produced inhibition of CYP1A2 (phenacetin O-deethylation), CYP2C9 (tolbutamide 4'-hydroxylation), CYP2D6 (dextromethorphan O-demethylation) and CYP3A4 (testosterone 6beta-hydroxylation) activities with IC50 = 40, 49, 213 and 32 microM respectively. Ki for propofol against all of these enzymes with the exception of CYP2D6, where propofol showed little inhibitory activity, was 30, 30 and 19 microM respectively for CYPs 1A2, 2C9 and 3A4. 2. Furafylline, sulphaphenazole, quinidine and ketoconazole, known selective inhibitors of CYPs 1A2, 2C9, 2D6 and 3A4 respectively, were much more potent than propofol having IC50 = 0.8, 0.5, 0.2 and 0.1 microM; furafylline and sulphaphenazole yielded Ki = 0.6 and 0.7 microM respectively. 3. The therapeutic blood concentration of propofol (20 microM; 3-4 microg/ml) together with the in vitro Ki estimates for each of the major human P450 enzymes have been used to estimate the extent of cytochrome P450 inhibition, which may be produced in vivo by propofol. This in vitro-in vivo extrapolation indicates that the degree of inhibition of CYP1A2, 2C9 and 3A4 activity which could theoretically be produced in vivo by propofol is relatively low (40-51%); this is considered unlikely to have any pronounced clinical significance. 4. Although propofol has now been used in > 190 million people since its launch in 1986, there are only single reports of possible drug interactions between propofol and either alfentanil or warfarin. Consequently, it is difficult to conclude from either the published literature or the ZENECA safety database whether there is any evidence to indicate that propofol produces clinically significant drug interactions through inhibition of cytochrome P450-related drug metabolism.

Anesthetics, Intravenous↗
PubMed1998

Enzyme-inducing effects of bicalutamide in mouse, rat and dog.

1. Bicalutamide, a non-steroidal antiandrogen, produced dose-related increases in total cytochrome P450 (P450) and aldrin epoxidase, but had no effect on ethoxyresorufin O-deethylase, when administered for 10 weeks at 0, 25, 75 and 150 mg/kg/day to the male dog. 2. In the male and female mouse, bicalutamide, administered orally at 75 mg/kg/day for 3 months, produced marked induction of total P450, ethoxycoumarin O-deethylase, pentoxyresorufin O-dealkylase and aldrin epoxidase. Immunoblotting showed that bicalutamide produced substantial induction of CYP2B isoforms, with lower increases in CYP3A. Immunohistochemistry of mouse liver sections also showed marked increases in the level of CYP2B isoforms, with an increase in the extent of distribution from centrilobular to panlobular; CYP3A isoforms were also increased, but to a lesser degree. 3. Bicalutamide, administered as 14 daily oral doses (250 mg/kg) to groups of male rats, produced increases primarily in ethoxycoumarin O-deethylase and erythromycin N-demethylase, together with smaller increases in ethoxyresorufin O-deethylase and pentoxyresorufin O-dealkylase; these changes were reversible within 7 days. Immunoblotting of microsomes and immunocytochemistry of liver sections showed that bicalutamide markedly induced CYP3A1, but had little effect on CYP2B1 in rat. Compared with dexamethasone, bicalutamide is a more selective inducer of CYP3A1 in rat. 4. Bicalutamide, administered to rats as 14 daily oral doses of 10 mg/kg, induced its own metabolism by stimulating both aromatic hydroxylation and direct glucuronidation. This effect was apparently offset by a concomitant decrease in hydrolysis of bicalutamide, resulting in no marked change in total amounts of dose eliminated over 2 days. 5. Although the secondary effects of enzyme induction result in thyroid hypertrophy and adenoma in rat and hepatocellular carcinoma in mouse following chronic administration of bicalutamide, these changes are considered to have little clinical relevance. In any case, bicalutamide does not produce enzyme induction in man at clinically relevant dose levels.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1998

Interlaboratory comparison of the assessment of P450 activities in human hepatic microsomal samples.

1. Although the importance of in vitro technology in supporting drug development is widely accepted, there is no real consensus about which approaches should be taken, which substrates should be used, or on the reliability and application of in vitro data. Consequently, as part of a collaborative project to characterize human liver with respect to the major forms of cytochrome P450, an interlaboratory comparison of the analysis of samples for form-specific activities was undertaken. 2. Microsomal fractions were isolated from five different human liver samples taken from the liver bank maintained at the Royal Postgraduate Medical School (RPMS). Aliquots from the five samples were sent to the 11 collaborating laboratories for characterization using their in-house, form-specific assays for cytochrome P450 activities. Although each laboratory assayed protein concentration, total cytochrome P450 content and enzyme activities were calculated using the protein estimation generated by RPMS to eliminate this possible source of variability. 3. With the exception of one laboratory, all estimates of protein concentration were similar (coefficient of variation, CoV, 9-13%) and the rank-order of the five samples was consistent across the laboratories. There was greater variability in the estimates of total cytochrome P450 content (CoV 28-43%), although again rank order of the samples across laboratories was fairly consistent. 4. The various laboratories used a number of different probe substrates, together with a range of conditions (substrate concentration, time of incubation, amount of protein), to assay for activity of CYP1A2, CYP2C9, CYP2D6, CYP2E1 and CYP3A4. However, apart from the occasional outlier, the five samples were ranked for activity of all these forms of cytochrome P450 with a high degree of consistency by the various laboratories and the choice of substrate had no appreciable effect on the ranking of the samples. 5. While this interlaboratory comparison has shown that greater consistency in the approach to in vivo determination of drug-metabolizing activity is desirable, there was little indication that any particular approach or substrate was superior to the others.

Aryl Hydrocarbon Hydroxylases↗
PubMed1996

Absence of hepatic enzyme induction in prostate cancer patients receiving 'Casodex' (bicalutamide).

The potential for hepatic enzyme induction by bicalutamide ('Casodex') was assessed in an open study in prostate cancer patients. A single, oral dose of antipyrine 1000 mg was given before and after 12 weeks' bicalutamide therapy [once daily 50 mg (n = 7) or 150 mg (n = 11)] and its pharmacokinetics and metabolism were determined. Plasma or saliva samples were taken for the measurement of antipyrine concentration. Urine samples were assayed for antipyrine and its three major metabolites. With bicalutamide 50 mg, plasma antipyrine concentrations were maximal between 2 and 4 h after administration, declined in a log-linear manner and were unaffected by bicalutamide therapy; with bicalutamide 150 mg, saliva antipyrine concentrations were maximal between 2 and 4 h, declined in a log-linear manner, and were also unaffected by bicalutamide therapy. Antipyrine half-life was 16.3% shorter after bicalutamide 50 mg (p < 0.05); a small decrease (13.5%) in half-life after bicalutamide 150 mg was not statistically significant. A small reduction (18.6%, p < 0.05) in the AUCinfinity for antipyrine was noted after bicalutamide 150 mg. A statistically significant reduction in antipyrine recovery was seen with the lower bicalutamide dose (23.7%, p < 0.05). The statistically significant changes were small in absolute terms and showed no dose-response relationship. Bicalutamide does not significantly induce the hepatic enzymes responsible for antipyrine metabolism and has no obvious potential for producing clinically significant drug interactions due to enzyme induction.

Aged↗
PubMed1996

Pharmacodynamics of ZM 241385, a potent A2a adenosine receptor antagonist, after enteric administration in rat, cat and dog.

4-(2-[7-Amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5] triazin-5-ylamino]ethyl)phenol (ZM 241385) is currently the most selective for the A2a adenosine receptor antagonist. This paper describes the in-vivo activity of ZM 241385 after administration by both oral and intraduodenal routes. In conscious spontaneously hypertensive rats, ZM 241385 (1-10 mg kg-1) selectively attenuated the mean arterial blood pressure response produced by exogenous adenosine (1 mg kg-1 min-1, i.v.) by up to 45% after oral administration. Activity of ZM 241385 was maintained for at least 6 h after 3 and 10 mg kg-1 (p.o.). In conscious normotensive cats, ZM 241385 attenuated the blood pressure responses to adenosine (0.6-1.0 mg kg-1, i.v.) by 94% after 10 mg kg-1 (p.o.) and by up to 74% after 0.3 mg kg-1 (i.v.). Duration of action of ZM 241385 up to 12 h (36% inhibition) was observed after 3 mg kg-1 (p.o.). In anaesthetized dogs and cats, ZM 241385, after intraduodenal administration (1-10 mg kg-1), produced a rapid (dose ratio 100-fold 15 min after administration of 10 mg kg-1 in the cat) and prolonged (dose ratio of 14 at 6 h after administration of 10 mg kg-1) attenuation of the vasodilatation responses to adenosine receptor stimulation. When administered by this route ZM 241385 was six times more potent than theophylline in the cat and at least twice as potent as theophylline in the dog. In conclusion, ZM 241385 is a potent, selective A2a adenosine receptor antagonist which is orally active, with a good duration of action by the enteric route in cat, rat and dog. It could therefore be used to evaluate the role of adenosine A2a receptors in the action of adenosine in-vivo.

Administration, Oral↗
PubMed1995

Enantioselective metabolism and pharmacokinetics of Casodex in the male rat.

1. Casodex, a non-steroidal antiandrogen, is a racemic mixture of R-Casodex, the pharmacologically active (-)-enantiomer, and S-Casodex, the inactive (+)-enantiomer. Single oral doses of pseudo-racemic 14C-Casodex (10 mg/kg), prepared from mixtures of either 14C-labelled R-Casodex and unlabelled S-Casodex, or 14C-S-Casodex and unlabelled R-Casodex, were administered to the intact and bile duct-cannulated male rat. 2. Neither enantiomer underwent stereochemical inversion, but the pharmacokinetics of Casodex showed marked enantioselectivity. 3. After dosing R-labelled Casodex, plasma concentrations of R-Casodex increased slowly to reach a peak of 3.50 +/- 0.05 micrograms/ml (mean +/- SEM) at 12 h and, thereafter, declined monoexponentially with an elimination half-life of 24 h. Plasma concentrations of S-Casodex rose rapidly to reach a much lower peak of 0.97 +/- 0.06 microgram/ml at 3 h and, thereafter, declined rapidly, although there were insufficient data to determine the half-life. R-Casodex had a much higher AUC0-24 (66 micrograms.h/ml) than S-Casodex (12 micrograms.h/ml). Plasma drug concentrations measured using an achiral assay were in very good agreement with the sum of the enantiomer concentrations throughout the profile. R-Casodex comprised 94% of the total plasma radioactivity at 12 h, decreasing to 75% at 120 h. 4. Plasma concentration data generated after administration of S-Casodex were similar to those observed after dosing R-labelled Casodex. S-Casodex comprised about 74% of the total plasma radioactivity at 6 h and only 41% at 24 h. 5. The urine of intact animals contained 36 +/- 2 and 48 +/- 3% of the dose respectively up to 48 and 120 h after dosing with R-labelled Casodex, and 33 +/- 4 and 34 +/- 4% respectively after dosing with S-labelled Casodex. The urine and bile of the cannulated rat contained 43 +/- 2 and 21 +/- 2% of the dose respectively up to 48 h after dosing with R-labelled Casodex and 37 (n = 2) and 50% respectively after dosing with S-labelled Casodex. 6. After dosing with R- or S-labelled Casodex, the urinary radioactivity consisted of the carboxylic acid metabolite formed by hydrolytic cleavage at the amide, whereas biliary radioactivity consisted of hydroxy-Casodex and Casodex, mainly conjugated with glucuronic acid. The clearance of R-Casodex by each of these pathways of metabolism was less than that of S-Casodex, with direct glucuronidation and hydroxylation showing greater enantioselectivity than hydrolysis.

Androgen Antagonists↗
PubMed1993

The effects on rat thyroid function of an hepatic microsomal enzyme inducer.

1. Following daily administration to male albino rats for 2 weeks, beta-naphthoflavone (25 and 60 mg kg-1, i.p.) and phenobarbitone (100 mg kg-1, p.o.) produced their characteristic patterns of induction of P450-related enzyme activities. beta-naphthoflavone also induced p-nitrophenol glucuronidation by 160% over controls, while phenobarbitone produced only a 45% induction of this conjugation activity. 2. beta-Naphthoflavone produced significant reductions in plasma thyroxine (T4) concentrations on days 4 and 16 and also decreased tri-iodothyronine (T3) on day 4. Thyroid-stimulating hormone (TSH) was significantly increased on day 16 by the higher dose of beta-naphthoflavone. Thyroid weight was significantly increased at both dose levels on day 16 and liver weight was significantly increased on both days 4 and 16. No histopathological changes were seen in the liver or pituitary, but 30% of the animals showed minimal to mild follicular epithelial hypertrophy of the thyroid gland. 3. Phenobarbitone had no effect on T4 concentrations, but significantly decreased T3 on day 4. TSH increased by 60% on day 16, but was not statistically significantly compared with controls. Thyroid weight was significantly increased on day 16 and liver weight was significantly increased on days 4 and 16. Mild to moderate thyroid follicular epithelial hypertrophy and moderate hepatocyte hypertrophy occurred in all animals. No histopathological changes were seen in the pituitary. 4. The early changes in T4 and/or T3 were probably due to increased hepatic clearance by induction of thyroxine glucuronidation with both compounds. Thyroid hypertrophy would be expected to follow as a result of activation of the hypothalamic-pituitary-thyroid axis.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Metabolism and enantioselective pharmacokinetics of Casodex in man.

1. Five healthy male volunteers received a single oral dose (50 mg; 42 microCi) of 14C-Casodex, a racemic compound, which has its antiandrogen activity predominantly in R-Casodex, the (-)-enantiomer, with little activity in S-Casodex, the (+)-enantiomer. 2. Plasma concentrations of R-Casodex increased slowly in all subjects to reach a peak of 559-970 ng/ml between 15 and 48 h after dosing and, thereafter, declined monoexponentially with a mean half-life of 4.2 days. Plasma concentrations of S-Casodex rose rapidly to reach a peak of 32-66 ng/ml within the first 2-5 h, and then declined monoexponentially with a mean half-life of 19 h. Plasma concentrations of the racemate were in very good agreement with the sum of the enantiomer concentrations throughout the study and were very similar to concentrations of total radioactivity over the first 4 days. 3. About 80% of the radioactive dose was recovered in urine (35.8 +/- 1.7%; mean +/- SEM) and faeces (42.6 +/- 2.9%) during a total collection over 9 days; this incomplete recovery was consistent with the slow elimination of R-Casodex. 4. T.l.c. of urine extracts indicated extensive metabolism of Casodex to two polar metabolites identified as the glucuronide conjugates of Casodex and hydroxy-Casodex; almost no parent compound was observed. Virtually all of the Casodex glucuronide excreted in urine during the first 2 days was derived from S-Casodex, consistent with the relatively low plasma concentrations and rapid elimination of this enantiomer. 5. T.l.c. of faecal extracts showed the presence of both Casodex and hydroxy-Casodex; these may have been eliminated in bile as the glucuronide conjugates, with subsequent hydrolysis in the intestinal tract.

Administration, Oral↗
PubMed1993

Metabolism of Casodex in laboratory animals.

1. Casodex, a non-steroidal antiandrogen, was eliminated primarily in faeces by rat, mouse, rabbit and dog. Rat, mouse and rabbit eliminated 20-30% of a single oral dose (8-25 mg/kg) in urine; only 3-4% was excreted in urine by dog (2.5 mg/kg). Oral absorption was about 80% in rat, mouse, rabbit and dog. 2. Most of the dose was recovered in 48 h from rat, mouse and rabbit. In rat, < 1% of the dose was exhaled as 14CO2 and < 1% remained in the carcass after 7 days. Recovery from dog was incomplete in 4 days but consistent with the long plasma elimination half-life of 7-7.5 days. Casodex was eliminated from rat plasma with a half-life of 17-21 h. 3. Examination of urine indicated extensive metabolism of Casodex and showed a marked species difference. In rat, mouse and dog, Casodex was cleaved at the amide to yield a carboxylic acid and an aromatic amine which subsequently underwent ring hydroxylation with sulphate conjugation. In rabbit, the major urinary metabolite was Casodex glucuronide, conjugated on the tertiary hydroxyl. 4. The major component in faeces of all species was unchanged Casodex; some hydroxy-Casodex was also observed in rat faeces. Analysis of rat and dog bile indicated that Casodex and hydroxy-Casodex were eliminated in bile primarily as glucuronide conjugates.

Absorption↗
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↗