Differential effects of hepatic microsomal enzyme inducing agents on liver blood flow

Yates, M S; Roberts, P. A.; Back, David; Crawford, Francesca E.

doi:10.1016/0006-2952(78)90336-2

Cited by 39 publications

(22 citation statements)

References 9 publications

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“…and AUCportal was 23% which gives an extraction ratio of 0.77; hence in the rat norethisterone is highly extracted. Plasma clearance was not significantly different from the previously determined value for total hepatic blood flow in the female rat (Yates et al, 1978). On theoretical grounds, phenobarbitone (as an hepatic enzyme inducer) should have no effect on plasma norethisterone concentrations following systemic intravenous administration, but should give a reduction in AUC (with no effect on half life) after bolus portal administration.…”

Section: Discussionmentioning

confidence: 52%

“…The extraction ratio was only increased by 1.3% (from 0.77 to 0.78). It is important to note that in female rats, phenobarbitone did not significantly increase total liver blood flow (Yates et al, 1978). We have previously shown (Back et al, 1978a) that the rate of delivery of norethisterone to the liver is an important determinant of systemic availability.…”

Section: Discussionmentioning

confidence: 72%

“…Back & Crawford, 1978), only a small fraction of the blood flowing through the portal vein is removed. After centrifugation of the blood samples, total radioactivity was determined in an aliquot (20 pl) of plasma; the remaining plasma was subjected to ether extraction for determination of free steroid and conjugates.…”

Section: Experimental Procedures In Ratsmentioning

confidence: 99%

“…Values for hepatic drug clearance (C1H) and intrinsic clearance (Cl1,,) in control and phenobarbitonetreated rats are given in barbitone treated female rats were previously derived (Yates, Hiley, Roberts, Back & Crawford, 1978).…”

Section: Ratsmentioning

confidence: 99%

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Phenobarbitone Interaction With Oral Contraceptive Steroids in the Rabbit and Rat

Back

Breckenridge

Crawford

et al. 1980

British J Pharmacology

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1 The effect of phenobarbitone on the single dose pharmacokinetics of the synthetic steroids, ethinyloestradiol (EE2) and norethisterone, has been studied in the rabbit and rat. 2 EE2 is subject to an extensive first pass effect (96%). The plasma clearance of EE2 approaches total hepatic blood flow. It is suggested that a secondary peak in EE2 plasma concentration time curves at 5 h is due to enterohepatic recycling. Phenobarbitone had no effect on plasma EE2 concentrations following intravenous administration and produced a variable decrease after oral administration. 3 In phenobarbitone-treated rabbits, following intravenous administration of norethisterone there was no significant change in the area under the curve (AUC) compared to controls. In contrast, following oral administration of norethisterone to treated rabbits, the AUC was 20% and the peak plasma concentration 17% of that in controls.4 The data in rabbits are consistent with drugs which are highly extracted by the liver. 5 In rats, phenobarbitone had no effect on plasma norethisterone concentrations following intravenous or hepatic portal (bolus) administration, but caused a decrease in systemic availability after both infusion into the portal vein (over a period of 5 min) and oral administration. 6 It is concluded that the rate of delivery of norethisterone to the liver is important in determining whether or not enzyme induction will cause an increased first pass effect. 7 Phenobarbitone caused an increase in conjugation of norethisterone in the gastrointestinal tract of rats.

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Section: Discussionmentioning

confidence: 52%

Section: Discussionmentioning

confidence: 72%

Section: Experimental Procedures In Ratsmentioning

confidence: 99%

Section: Ratsmentioning

confidence: 99%

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Phenobarbitone Interaction With Oral Contraceptive Steroids in the Rabbit and Rat

Back

Breckenridge

Crawford

et al. 1980

British J Pharmacology

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“…Yet in experimental animals in this study and others (Alberts et al, 1976; the addition of this enzyme inducer markedly reduces the total amount of alkylating metabolites from CTX, and its antitumour effects. It should be borne in mind, however, that phenobarbital administration also increases hepatic size and blood flow (Yates et al, 1978) and bile flow (Klaassen,1]969). Conversely, experimental microsomal enzyme inhibitors such as SKF-525a (diethylaminoethyldiphenyl valerate) depress hepatic blood flow (Hakim & Fujimoto, 1971) and can reverse phenobarbital induction and restore CTX antitumour activity (Alberts et al, 1976).…”

Section: Resultsmentioning

confidence: 99%

Cimetidine enhancement of cyclophosphamide antitumour activity

Dorr¹,

Alberts²

1982

Br J Cancer

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Summary.-Male DBA2 mice were given 106 P-388 leukaemic cells i.p. and cimetidine (CMT) at 100 mg/kg 1 day for 10 days, or as a single 100mg/kg injection 30 min before cyclophosphamide (CTX). CMT significantly prolonged the survival of groups of mice receiving 50, 100 and 200 mg/kg of CTX 3 days after tumour inoculation.Median survival increased by 5-5 days (P <0-05), 10 days (P <0.05) and 13 days (P < 0.05) respectively. The addition of CMT had the effect of roughly doubling the CTX dose, without increasing the lethality. CMT produced the only long-term survival seen in the study (1-2/10) CMT alone had no apparent antitumour activity. CMT significantly prolonged mean pentobarbital sleep to 28-6-60 min vs only 10 min for phenobarbital treated mice. Both CMT regimens increased the plasma concentration time products for CTX-induced metabolites (NBP) by about 1-3 fold (in contrast to a 33% reduction with phenobarbital). On average the single-dose CMT regimen produced the greatest effect on survival, on pentobarbital sleep duration and on total NBP reactive species. Probable mechanisms for the CMT-CTX interaction include competitive microsomal enzyme inhibition and/or acutely depressed hepatic blood flow. Caution should be used in combining CMT with full doses of CTX and any other highly metabolized antineoplastic agents in man.

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Effects of enzyme inducers or inhibitors on the pharmacokinetics of intravenous parathion in rats

Hurh¹,

Lee²,

Lee³

et al. 2000

Biopharm. Drug Dispos.

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In order to find what form of hepatic cytochrome P450 (CYP) is involved in the metabolism of parathion to form paraoxon, rats were pretreated with the enzyme inhibitors, such as SKF 525-A and ketoconazole or enzyme inducers, such as dexamethasone, isoniazid, phenobarbital, and 3-methylcholanthrene. Parathion, 3 mg/kg, was infused in 1 min via the jugular vein. In rats pretreated with SKF 525-A or ketoconazole, nonspecific CYP inhibitors, the area under the plasma concentration-time curve from time zero to time infinity (AUC) and total body clearance (Cl) of parathion were significantly greater and slower, respectively, than those in respective control rats, suggesting that parathion was metabolized by CYPs. In rats pretreated with dexamethasone (CYP3A23 inducer), the AUC was significantly smaller (41.5 compared with 52.5 microg min/mL), Cl was significantly faster (72.2 compared with 57.1 mL/min/kg), and the amounts and/or tissue-to-plasma ratios of parathion was significantly (or tended to be) smaller than those in control rats. However, the pharmacokinetic parameters of parathion were not significantly different after pretreatment with other enzyme inducers compared with respective control rats. The above data suggested that parathion was metabolized to paraoxon by dexamethasone-inducible CYP3A23, the induction of which was confirmed by Western blot analysis. This was supported by in vitro intrinsic clearance (Cl(int)) of parathion to form paraoxon in hepatic microsomal fraction; the Cl(int) in rats pretreated with dexamethasone was significantly faster (0.0900 compared with 0.0290 mL/min/mg protein) than that in control rats.

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Differential effects of hepatic microsomal enzyme inducing agents on liver blood flow

Cited by 39 publications

References 9 publications

Phenobarbitone Interaction With Oral Contraceptive Steroids in the Rabbit and Rat

Phenobarbitone Interaction With Oral Contraceptive Steroids in the Rabbit and Rat

Cimetidine enhancement of cyclophosphamide antitumour activity

Effects of enzyme inducers or inhibitors on the pharmacokinetics of intravenous parathion in rats

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