Selectivity and dose‐dependency of the inhibitory effect of propranolol on theophylline metabolism in man.

Miners, John O.; Wing, L. M. H.; Lillywhite, K. J.; Robson, Richard

doi:10.1111/j.1365-2125.1985.tb05064.x

Cited by 32 publications

(19 citation statements)

References 19 publications

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“…In man, the enzymes involved in theophylline metabolism have been investigated by in vivo studies using known inducers and inhibitors of the P-450 system (Grygiel & Birkett, 1981;Grygiel et al, 1984;Robson et al, 1984;Miners et al, 1985;Grygiel et al, 1979). These studies provide inferential evidence that cytochrome P-450 system is the enzyme involved in the metabolism of theophylline in man and are consistent with the more direct evidence in rat liver slices and rat microsomes (Lohman & Miech, 1976).…”

Section: Introductionmentioning

confidence: 73%

Characterisation of theophylline metabolism in human liver microsomes.

Robson

Matthews

Miners

et al. 1987

Brit J Clinical Pharma

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119

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1 A radiometric high performance liquid chromatographic method is described for the assay of theophylline metabolism in vitro by the microsomal fraction of human liver. 2 Formation of the three metabolites of theophylline (3-methylxanthine, 1-methylxanthine and 1 ,3-dimethyluric acid) were linear with protein concentrations to 4 mg mland with incubation times up to 180 min. 3 The coefficients of variation for the formation of 3-methylxanthine, 1-methylxanthine and 1,3-dimethyluric acid were 1.2%, 1% and 1.6%, respectively. 4 Theophylline is metabolised by microsomal enzymes with a requirement for NADPH. 5 The mean (n = 7) Km values for 1-demethylation, 3-demethylation and 8-hydroxylation were 545, 630 and 788 FtM, respectively, and the mean Vmax values were 2.65, 2.84 and 11.23 pmol min-' mg-', respectively. 6 There was a high correlation between the Km and Vmax values for the two demethylation pathways suggesting that the demethylations are performed by the same enzyme. 7 Overall the in vitro studies are consistent with the in vivo results which suggest the involvement of two cytochrome P-450 isozymes in the metabolism of theophylline.Keywords theophylline metabolism cytochrome P-450 in vitro

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Section: Introductionmentioning

confidence: 73%

Characterisation of theophylline metabolism in human liver microsomes.

Robson

Matthews

Miners

et al. 1987

Brit J Clinical Pharma

Self Cite

119

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“…Similarly, studies with unusually high or low doses of perpetrators were excluded.For example, propranolol may be classified as a moderate inhibitor of CYP1A2 based on its interaction at 720 mg day -1 with theophylline [26]. However, using a criteria-based assessment,propranolol is a weak inhibitor of CYP1A2 as typical doses have minor impact on theophylline clearance [26]. 5.…”

Section: Cyp Inhibitorsmentioning

confidence: 99%

Perpetrators of pharmacokinetic drug–drug interactions arising from altered cytochrome P450 activity: a criteria‐based assessment

Polasek

Lin

Miners

et al. 2011

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Many drugs inhibit or induce cytochrome P450 enzymes (CYP) to cause clinically significant changes in the concentrations of other drugs, i.e.'perpetrate' pharmacokinetic drug-drug interactions (PK-DDIs).• Tables that list the substrates, inhibitors and inducers of CYP are common, but they lack consistency and are constructed from evidence of variable quality. WHAT THIS STUDY ADDS• This is the first study to catalogue important perpetrators of PK-DDIs using objective criteria and clinical pharmacokinetic drug interaction studies. This information is intended to inform clinical decisions on PK-DDIs.• Existing tables of CYP inhibitors and inducers have low sensitivity and low positive predictive value in identifying the major perpetrators of PK-DDIs. • Several drugs were identified which potentially perpetrate CYP-mediated PK-DDIs, but quality clinical pharmacokinetic interaction studies are lacking. This information may be used to inform future research. AIMSTo catalogue the perpetrators of CYP-mediated pharmacokinetic drug-drug interactions (PK-DDIs) using clinically relevant criteria, and to compare this with an analogous catalogue. METHODSCandidate inhibitors and inducers of CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A ('perpetrators') were evaluated using published clinical pharmacokinetic interaction studies. Studies were selected on the basis of Նsix human subjects, use of a validated in vivo probe substrate for the CYP enzyme, and clinically relevant dosing. Inhibitors were described according to the FDA classifications of strong, moderate or weak, whereas inducers were classified as major (Նtwofold decrease in AUC) or weak (

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“…Nonselective P-adrenoceptor blockade with propranolol consistently decreases the systemic clearance of theophylline by 30-40% (Conrad & Nyman, 1980;Miners et al, 1985;Lombardi et al, 1987). The data reporting the effects that atenolol, a cardioselective renally eliminated ,3-adrenoceptor blocker, has on hepatic metabolic processes are inconclusive.…”

Section: Introductionmentioning

confidence: 99%

“…This effect, however, is not consistent among all 3-adrenoceptor blocking drugs. For example, propranolol, a lipophilic nonselective P-adrenoceptor blocker, consistently reduces the clearance of antipyrine (Bax et al, 1981;Kessler et al, 1978;Daneshmend & Roberts, 1982) and theophylline (Conrad & Nyman, 1980;Miners et al, 1985;Lombardi et al, 1987). Metoprolol, a lipophilic selective 3-adrenoceptor blocker, does not affect antipyrine clearance to the same extent as propranolol (Bax et al, 1981;Kirch et al, 1984) and influences theophylline clearance only in smoking subjects (Conrad & Nyman, 1980).…”

Section: Introductionmentioning

confidence: 99%