The effect of pretreatment with cimetidine on the bioavailability and disposition of atenolol and metoprolol.

Jj, Houtzagers; Streurman, O.; Regårdh, C G

doi:10.1111/j.1365-2125.1982.tb04935.x

Cited by 19 publications

(7 citation statements)

References 22 publications

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“…These characteristics bestow on atenolol clinical relevance as a probe substrate more sensitive than metformin for assessing hOCT2 inhibitors in vitro. However, available DDI data did not suggest a positive in vivo interaction for atenolol and cimetidine (Houtzagers et al, 1982;Kirch et al, 1982;Mutschler et al, 1984). The total renal clearance of atenolol (∼168 ml/min) is only 1.4-fold of its glomerular filtration clearance (∼120 ml/min), suggesting that active tubular secretion only contributes to a minor (∼30%) part of atenolol total clearance.…”

Section: Discussionmentioning

confidence: 97%

Impact of Substrate-Dependent Inhibition on Renal Organic Cation Transporters hOCT2 and hMATE1/2-K-Mediated Drug Transport and Intracellular Accumulation

Yin

Duan

Wang

2016

J Pharmacol Exp Ther

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Renal transporter-mediated drug-drug interactions (DDIs) are of significant clinical concern, as they can adversely impact drug disposition, efficacy, and toxicity. Emerging evidence suggests that human renal organic cation transporter 2 (hOCT2) and multidrug and toxin extrusion proteins 1 and 2-K (hMATE1/2-K) exhibit substrate-dependent inhibition, but their impact on renal drug secretion and intracellular accumulation is unknown. Using metformin and atenolol as the probe substrates, we found that the classic inhibitors (e.g., cimetidine) of renal organic cation secretion were approximately 10-fold more potent for hOCT2 when atenolol was used, suggesting that atenolol is a more sensitive in vitro substrate for hOCT2 than metformin. In contrast, inhibition of hMATE1/2-K was influenced much less by the choice of substrate. Cimetidine is a much more potent inhibitor for hMATE1/2-K when metformin is the substrate but acts as an equally potent inhibitor of hOCT2 and hMATE1/2-K when atenolol is the substrate. Using hOCT2/hMATE1 doubletransfected Madin-Darby canine kidney cells, we evaluated the impact of substrate-dependent inhibition on hOCT2/hMATE1-mediated transepithelial flux and intracellular drug accumulation. At clinically relevant concentrations, cimetidine dose dependently inhibited basal-to-apical flux of atenolol and metformin but impacted their intracellular accumulation differently, indicating that substrate-dependent inhibition may shift the major substrate-inhibitor interaction site between apical and basolateral transporters. Cimetidine is effective only when applied to the basal compartment. Our findings revealed the complex and dynamic nature of substrate-dependent inhibition of renal organic cation drug transporters and highlighted the importance of considering substrate-dependent inhibition in predicting transporter-mediated renal drug interaction, accumulation, and toxicity.

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Section: Discussionmentioning

confidence: 97%

Impact of Substrate-Dependent Inhibition on Renal Organic Cation Transporters hOCT2 and hMATE1/2-K-Mediated Drug Transport and Intracellular Accumulation

Yin

Duan

Wang

2016

J Pharmacol Exp Ther

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“…Kirch et al (1982) gave metoprolol loomg twice daily to 6 male subjects together with cimetidine and found that the AUC of metoprolol increased from 1167 ± 192 to 1885 ± 343 ~g/L • h (p < 0.05) with no change in half-life or exerciseinduced tachycardia. In contrast, Houtzagers et al (1982) gave 7 subjects aged 29 to 68 years with underlying pathology a single oral dose of metoprolol 100mg on 2 occasions, alone and after long term administration of cimetidine (1 g/day). The AUC of metoprolol did not differ between the 2 occasions (3.98 ± 1.18 versus 4.2 ± 1.1 ~molfL·h).…”

Section: Metapralalmentioning

confidence: 91%

“…Daneshmend & (1984) 0.85 ± 0.13 1.41 ± 0.32b t (60) 1.17 ± 0.47 1.89 ± 0.84 b t (62) Kirch et al (1982) 1.1 ± 0.8 1.1 ± 0.7 Houtzagers et al (1982) 2.93 ± 0.95 3.2 ± 1.26 Duchin et al (1984) Kirch et al (1982) 0.53 ± 0.35 0.78 ± 0.39b t (46) Duchin et al (1984) ~ (32) Donn et al (1984) tional, these data are consistent with the findings of Reimann and co-workers. When Duchin et al (1984) gave a single dose of propranolol 80mg to a group of subjects, cimetidine increased the propranolol AUe from 531 to 775 Ilg/L· h (p < 0.05).…”

Section: Propranololmentioning

confidence: 97%

Pharmacokinetic Interactions of Cimetidine 1987

Somogyi

Muirhead

1987

Clinical Pharmacokinetics

184

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The number of studies on drug interactions with cimetidine has increased at a rapid rate over the past 5 years, with many of the interactions being solely pharmacokinetic in origin. Very few studies have investigated the clinical relevance of such pharmacokinetic interactions by measuring pharmacodynamic responses or clinical endpoints. Apart from pharmacokinetic studies, invariably conducted in young, healthy subjects, there have been a large number of in vitro and in vivo animal studies, case reports, clinical observations and general reviews on the subject, which is tending to develop an industry of its own accord. Nevertheless, where specific mechanisms have been considered, these have undoubtedly increased our knowledge on the way in which humans eliminate xenobiotics. There is now sufficient information to predict the likelihood of a pharmacokinetic drug-drug interaction with cimetidine and to make specific clinical recommendations. Pharmacokinetic drug interactions with cimetidine occur at the sites of gastrointestinal absorption and elimination including metabolism and excretion. Cimetidine has been found to reduce the plasma concentrations of ketoconazole, indomethacin and chlorpromazine by reducing their absorption. In the case of ketoconazole the interaction was clinically important. Cimetidine does not inhibit conjugation mechanisms including glucuronidation, sulphation and acetylation, or deacetylation or ethanol dehydrogenation. It binds to the haem portion of cytochrome P-450 and is thus an inhibitor of phase I drug metabolism (i.e. hydroxylation, dealkylation). Although generally recognised as a nonspecific inhibitor of this type of metabolism, cimetidine does demonstrate some degree of specificity. To date, theophylline 8-oxidation, tolbutamide hydroxylation, ibuprofen hydroxylation, misonidazole demethylation, carbamazepine epoxidation, mexiletine oxidation and steroid hydroxylation have not been shown to be inhibited by cimetidine in humans but the metabolism of at least 30 other drugs is affected. Recent evidence indicates negligible effects of cimetidine on liver blood flow. Cimetidine reduces the renal clearance of drugs which are organic cations, by competing for active tubular secretion in the proximal tubule of the kidney, reducing the renal clearances of procainamide, ranitidine, triamterene, metformin, flecainide and the active metabolite N-acetylprocainamide. This previously unrecognised form of drug interaction with cimetidine may be clinically important for both parent drug, and metabolites which may be active.(ABSTRACT TRUNCATED AT 400 WORDS)

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“…The co-administration of the H2-receptor antagonist cimetidine, another commonly used agent, has been shown by some workers to increase the bioavailability of the lipophilic cardioselective 3-adrenoceptor blocker metoprolol, but not that of the hydrophilic cardioselective B3-adrenoceptor blocker atenolol (Kirch et al, 1981). This work has not been confirmed by Houtzagers et al (1982).…”

Section: Introductionmentioning

confidence: 94%

The effect of cimetidine on the relative cardioselectivity of atenolol and metoprolol in asthmatic patients.

Ellis¹,

Hussain²,

Webb³

et al. 1984

Brit J Clinical Pharma

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1 The effects of chronic cimetidine therapy on the pharmacodynamic properties of atenolol and metoprolol were assessed in eight asthmatic patients using a placebocontrolled trial. 2 When atenolol and metoprolol were administered at doses which achieved an equivalent degree of /31-adrenoceptor blockade, metoprolol caused a significantly greater reduction in mean forced expiratory volume in one second (FEVy). This demonstrates the greater cardioselectivity of atenolol. 3 The reductions in mean FEV1 induced by either atenolol or metoprolol were each unaffected by cimetidine.4 Plasma levels of each of the ,8-adrenoceptor blockers were not affected by the addition of cimetidine.5 The FEV, in one patient was further reduced when cimetidine was administered with metoprolol, although there was no corresponding change in plasma levels of drug. In this patient there was no such further reduction in FEV1 with atenolol. 6 This study has not provided evidence for a pharmacodynamic interaction between cimetidine and either atenolol or metoprolol, but further studies are indicated.

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The effect of pretreatment with cimetidine on the bioavailability and disposition of atenolol and metoprolol.

Cited by 19 publications

References 22 publications

Impact of Substrate-Dependent Inhibition on Renal Organic Cation Transporters hOCT2 and hMATE1/2-K-Mediated Drug Transport and Intracellular Accumulation

Impact of Substrate-Dependent Inhibition on Renal Organic Cation Transporters hOCT2 and hMATE1/2-K-Mediated Drug Transport and Intracellular Accumulation

Pharmacokinetic Interactions of Cimetidine 1987

The effect of cimetidine on the relative cardioselectivity of atenolol and metoprolol in asthmatic patients.

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