Failure of ‘therapeutic’ doses of beta‐adrenoceptor antagonists to alter the disposition of tolbutamide and lignocaine.

Miners, John O.; Wing, L. M. H.; Lillywhite, K. J.; Smith, Kenneth J.

doi:10.1111/j.1365-2125.1984.tb02555.x

Cited by 27 publications

(7 citation statements)

References 20 publications

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“…Whereas Conrad et al (1983) showed that metoprolol lowered the clearance of lignocaine significantly by about 25%, more recent studies found no significant effects (Jordo et al, 1984;Miners et al, 1984). However, it is possible that the power of these studies was not sufficient to detect the predicted small decrease in the clearance of lignocaine due to enzyme inhibition.…”

Section: Discussionmentioning

confidence: 95%

The impairment of lignocaine clearance by propranolol‐major contribution from enzyme inhibition.

Bax¹,

Tucker²,

Lennard³

et al. 1985

Brit J Clinical Pharma

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1 To account for a 40% lowering of the systemic clearance of lignocaine by propranolol treatment it has been proposed that propranolol reduces liver blood flow by 25% and causes a 50% decrease in the intrinsic clearance of lignocaine by enzyme inhibition. 2 In theory, the contribution of direct enzyme inhibition is best evaluated using oral administration of lignocaine when models of hepatic drug clearance predict that propranolol could increase the AUCP0 of lignocaine by 100-140%.3 This hypothesis was tested in six healthy men who received 200 mg lignocaine HCl.H20 orally with and without propranolol pre-treatment (80 mg twice daily for 3 days). Propranolol treatment increased the mean plasma AUCpO of lignocaine by 113 ± 58 s.d.% (P < 0.005); it increased the peak plasma lignocaine concentration by 79 ± 50 s.d.% (P < 0.025) and it prolonged the elimination half-life of lignocaine by 20 + 13 s.d.% (P < 0.05). 4 Propranolol treatment lowered indocyanine green clearance by 11 + 15 s.d.%, but this change was not significant statistically. 5 These experimental results are in accord with the theoretical predictions suggesting that propranolol lowers the systemic clearance of lignocaine mainly by direct inhibition of its metabolism rather than by a lowering of the hepatic blood flow.

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Section: Discussionmentioning

confidence: 95%

The impairment of lignocaine clearance by propranolol‐major contribution from enzyme inhibition.

Bax¹,

Tucker²,

Lennard³

et al. 1985

Brit J Clinical Pharma

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“…Available evidence from interaction studies indicates that β‐adrenoceptor antagonists [110], dextropropoxyphene [111], diltiazem [112], enoxacin [113], erythromycin [81, 114], metronidazole [115], olanzapine [116] and omeprazole [117, 118] are all unlikely to inhibit CYP2C9 activity in vivo .…”

Section: Factors Affecting Cyp2c9 Activitymentioning

confidence: 99%

Cytochrome P4502C9: an enzyme of major importance in human drug metabolism

Miners

Birkett

1998

Brit J Clinical Pharma

729

533

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Accumulating evidence indicates that CYP2C9 ranks amongst the most important drug metabolizing enzymes in humans. Substrates for CYP2C9 include fluoxetine, losartan, phenytoin, tolbutamide, torsemide, S-warfarin, and numerous NSAIDs. CYP2C9 activity in vivo is inducible by rifampicin. Evidence suggests that CYP2C9 substrates may also be induced variably by carbamazepine, ethanol and phenobarbitone. Apart from the mutual competitive inhibition which may occur between alternate substrates, numerous other drugs have been shown to inhibit CYP2C9 activity in vivo and/or in vitro. Clinically significant inhibition may occur with coadministration of amiodarone, fluconazole, phenylbutazone, sulphinpyrazone, sulphaphenazole and certain other sulphonamides. Polymorphisms in the coding region of the CYP2C9 gene produce variants at amino acid residues 144 (Arg144Cys) and 359 (Ile359Leu) of the CYP2C9 protein. Individuals homozygous for Leu359 have markedly diminished metabolic capacities for most CYP2C9 substrates, although the frequency of this allele is relatively low. Consistent with the modulation of enzyme activity by genetic and other factors, wide interindividual variability occurs in the elimination and/or dosage requirements of prototypic CYP2C9 substrates. Individualisation of dose is essential for those CYP2C9 substrates with a narrow therapeutic index.

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“…For example, the various pathways of theophylline metabolism were shown to be induced by rifampicin, sulphinpyrazone and cigarette smoking, inhibited by propranolol and cimetidine and unaffected by sulphaphenazole 2–4 . While also induced by rifampicin, tolbutamide metabolic clearance was, in contrast, inhibited by sulphinpyrazone and sulphaphenazole and unaffected by cigarette smoking, propranolol and cimetidine 5–7 . In the course of these studies, an individual was identified whose tolbutamide metabolic clearance was only 15% of the population mean 8 .…”

Section: Introductionmentioning

confidence: 99%

“…[2][3][4] While also induced by rifampicin, tolbutamide metabolic clearance was, in contrast, inhibited by sulphinpyrazone and sulphaphenazole and unaffected by cigarette smoking, pro-pranolol and cimetidine. [5][6][7] In the course of these studies, an individual was identified whose tolbutamide metabolic clearance was only 15% of the population mean. 8 Despite impaired tolbutamide elimination, indices of metabolic clearance for theophylline and debrisoquine, the latter known to exhibit genetic polymorphism, were close to the respective population averages.…”

Section: Introductionmentioning

confidence: 99%

Evolution of drug metabolism: Hitchhiking the technology bandwagon

Miners¹

2002

Clin Exp Pharma Physio

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1. The application of a range of established and emerging technologies and experimental approaches has allowed investigation of cytochrome P450 (CYP) and uridine diphosphate-glucuronosyltransferase (UGT) at the functional, structural and molecular levels to address questions of therapeutic relevance, particularly the wide interindividual variability in metabolic clearance characteristic of drugs and chemicals metabolized by these enzymes. 2. Studies in vivo initially identified the various factors that contribute to interindividual variability. Subsequently, human liver microsomal kinetic approaches, together with the cloning and functional characterization of recombinant CYP and UGT isoforms, led to the development of in vitro strategies that allowed the qualitative prediction of those factors likely to alter the metabolic clearance of a given compound in vivo. More recently, computer (in silico) modelling has been used to complement the laboratory based procedures. 3. The application of molecular biological approaches additionally allowed identification of the mutations responsible for CYP and UGT genetic polymorphism and, in some instances, the domains and individual amino acids that confer isoform substrate and inhibitor selectivities. Homology models, developed using X-ray crystallographic data as the template, potentially enable prediction of the functional consequences of altered CYP structure. 4. The rapid advances occurring in genomics, proteomics, gene expression analysis and computer modelling will allow further unravelling of the complexities of drug metabolism and improved prospects for the individualization of drug therapy.

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Failure of ‘therapeutic’ doses of beta‐adrenoceptor antagonists to alter the disposition of tolbutamide and lignocaine.

Cited by 27 publications

References 20 publications

The impairment of lignocaine clearance by propranolol‐major contribution from enzyme inhibition.

The impairment of lignocaine clearance by propranolol‐major contribution from enzyme inhibition.

Cytochrome P4502C9: an enzyme of major importance in human drug metabolism

Evolution of drug metabolism: Hitchhiking the technology bandwagon

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