Interaction between the beta‐adrenoceptor blockers metoprolol and atenolol with amitriptyline and their effects on oxidative liver metabolism.

Kirch, Wilhelm; Spahn, H.; Kitteringham, NR; Hutt, HJ; Mutschler, E.; Ohnhaus, E. E.

doi:10.1111/j.1365-2125.1984.tb02430.x

Cited by 11 publications

(7 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In high noncardioselective doses, 200 mg per day, atenolol has been shown to decrease the clearance of antipyrine (Daneshmend & Roberts, 1982). Kirch et al (1984), while not showing statistical significance, found similar changes in mean antipyrine clearance. Significance was not achieved because of the small number of volunteers studied (n = 6) and the large variability observed in antipyrine clearance during the control phase (CV = 50.2%).…”

Section: Introductionmentioning

confidence: 68%

“…The data reporting the effects that atenolol, a cardioselective renally eliminated ,3-adrenoceptor blocker, has on hepatic metabolic processes are inconclusive. Some reports indicate that atenolol does not influence antipyrine clearance (Tucker et al, 1982;Kirch et al, 1984), while others clearly show an inhibitory effect (Daneshmend & Roberts, 1982;AdamskaDyniewska et al, 1986). Determining if atenolol can inhibit the clearance of theophylline would clarify the effects that atenolol has on the pharmacokinetics of drugs eliminated by hepatic metabolism.…”

Section: Introductionmentioning

confidence: 99%

“…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). The less lipophilic ,-adrenoceptor blockers, such as nadolol and atenolol, alter antipyrine clearance in an inconsistent manner (Tucker et al, 1982;Daneshmend & Roberts, 1982;Kirch et al, 1984;Adamska-Dyniewska et al, 1986).…”

Section: Introductionmentioning

confidence: 99%

“…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). The less lipophilic ,-adrenoceptor blockers, such as nadolol and atenolol, alter antipyrine clearance in an inconsistent manner (Tucker et al, 1982;Daneshmend & Roberts, 1982;Kirch et al, 1984;Adamska-Dyniewska et al, 1986). In high noncardioselective doses, 200 mg per day, atenolol has been shown to decrease the clearance of antipyrine (Daneshmend & Roberts, 1982).…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Lack of effect of atenolol on the pharmacokinetics of theophylline.

Cerasa¹,

Bertino²,

Ludwig³

et al. 1988

Brit J Clinical Pharma

View full text Add to dashboard Cite

show abstract

Section: Introductionmentioning

confidence: 68%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Lack of effect of atenolol on the pharmacokinetics of theophylline.

Cerasa¹,

Bertino²,

Ludwig³

et al. 1988

Brit J Clinical Pharma

View full text Add to dashboard Cite

show abstract

“…All the literature clinical interaction studies used a crossover design and between 5 and 24 subjects and were at steady state for inhibitor with the exception of Bergstrom et al (1992) and at steady state for substrate except for the following studies: Brøsen and Gram (1989), Hamelin et al (2000), Johnson and Burlew (1996), Tateishi et al (1989), and Spina et al (1993), in which the interaction was determined following a single dose. CYP2D6 poor metabolizers were excluded via either genotyping or phenotyping assessment except in the following studies in which CYP2D6 status was not determined: Bergstrom et al (1992), Donn et al (1984), Keech et al (1986), Kirch et al (1982Kirch et al ( , 1984, Kowey et al (1989), Hermann et al (1992), Henry et al (1987), Hunt et al (1990) (IC 50,u ) values against the eight major human hepatic P450s (rCYP1A2, rCYP2B6, rCYP2C8, rCYP2C9, rCYP2C19, rCYP2D6, rCYP3A4, and rCYP3A5) for a selection of compounds that have been investigated in clinical studies as perpetrators of DDIs against predominantly CYP2D6 substrates. The in vitro CYP2D6 potency ranged from 20 nM for propafenone and quinidine to 91 M for cimetidine.…”

Section: Methodsmentioning

confidence: 99%

Integrated in Vitro Analysis for the in Vivo Prediction of Cytochrome P450-Mediated Drug-Drug Interactions

McGinnity¹,

Waters²,

Tucker³

et al. 2008

Drug Metab Dispos

View full text Add to dashboard Cite

ABSTRACT:Unbound IC 50 (IC 50,u ) values of 15 drugs were determined in eight recombinantly expressed human cytochromes P450 (P450s) and human hepatocytes, and the data were used to simulate clinical area under the plasma concentration-time curve changes (␦AUC) on coadministration with prototypic CYP2D6 substrates. Significant differences in IC 50,u values between enzyme sources were observed for quinidine (0.02 M in recombinant CYP2D6 versus 0.5 M in hepatocytes) and propafenone (0.02 versus 4.1 M). The relative contribution of individual P450s toward the oxidative metabolism of clinical probes desipramine, imipramine, tolterodine, propranolol, and metoprolol was estimated via determinations of intrinsic clearance using recombinant P450s (rP450s). Simulated ␦AUC were compared with those observed in vivo via the ratios of unbound inhibitor concentration at the entrance to the liver to inhibition constants determined against rP450s ([I] in,u /K i ) and incorporating parallel substrate elimination pathways. For this dataset, there were 20% false negatives (observed ␦AUC > 2, predicted ␦AUC < 2), 77% correct predictions, and 3% false positives. Thus, the [I] in,u /K i approach appears relatively successful at estimating the degree of clinical interactions and can be incorporated into drug discovery strategies. Using a Simcyp ADME (absorption, metabolism, distribution, elimination) simulator (Simcyp Ltd., Sheffield, UK), there were 3% false negatives, 94% correct simulations, and 3% false positives. False-negative predictions were rationalized as a result of mechanism-based inhibition, production of inhibitory metabolites, and/or hepatic uptake. Integrating inhibition and reaction phenotyping data from automated rP450 screens have shown applicability to predict the occurrence and degree of in vivo drug-drug interactions, and such data may identify the clinical consequences for candidate drugs as both "perpetrators" and "victims" of P450-mediated interactions.Inhibition of cytochrome P450 (P450) metabolism is recognized as one of the more prevalent mechanisms of clinical drug-drug interactions (DDIs) and may result in serious clinical and toxicological consequences (Nelson, 2002). During the past 2 decades, both in vitro and in vivo assessments of the P450 inhibition potential and disposition of drugs have led to a relatively thorough appreciation of the underlying reasons for certain drug combinations resulting in significant clinical outcomes. Application of this knowledge has led researchers to propose strategies that assess the potential of new chemical entities to cause clinical DDIs via inhibition of P450 metabolism. As a result, in the past decade or so, in vitro screens that determine the degree of P450 inhibition have become commonplace in drug discovery screening cascades. These screens are used to evaluate and optimize potential candidate drugs and to prioritize and design suitable clinical studies.In vitro-in vivo extrapolation (IVIVE) strategies used for P450 inhibition-mediated DDIs range from simple bu...

show abstract

Urinary 6?-hydroxycortisol: a validated test for evaluating drug induction or drug inhibition mediated through CYP3A in humans and in animals

Galteau

Shamsa

2003

European Journal of Clinical Pharmacology

144

116

View full text Add to dashboard Cite

6beta-Hydroxycortisol (6beta-OHF) urinary excretion has, for a long time, been considered a marker of drug induction and, more recently, of drug inhibition in humans and in laboratory animals, but its specificity is still under debate. In this work, we review 277 papers devoted to 6beta-OHF urinary excretion. We have evaluated factors that could modify 6beta-OHF excretion and, thus, could explain contradictory results. We have examined the effect of the analytical techniques on physiological values. Intra- and inter-individual variability and the effect of circadian rhythms on urinary excretion of 6beta-OHF as well as cortisol and 17-hydroxycorticosteroids have been evaluated. We also give an overview of drugs that induce, inhibit or have no effect on 6beta-OHF. For inducing and inhibiting drugs, we calculated the ranges of variation of 6beta-OHF excretion from the results indicated in the different papers. This work was done for well-known inducers, such as anticonvulsants, but also for other inducing or inhibiting drugs found in the literature. The time-course of variation in 6beta-OHF excretion when different drugs are co-administered was also investigated. The potential relationship between cytochrome P(450) 3A4 (CYP3A4) polymorphism and 6beta-OHF excretion was studied. Finally, the interest of 6beta-OHF urinary excretion was compared with that of other tests proposed to measure CYP3A4 activity. This review demonstrates that 6beta-OHF urinary excretion is a good test to evaluate drug-metabolising enzyme inducing or inhibiting properties of drugs when the subjects are their own controls, but this test is not reliable enough to measure actual CYP3A4 activity.

show abstract

Interaction between the beta‐adrenoceptor blockers metoprolol and atenolol with amitriptyline and their effects on oxidative liver metabolism.

Cited by 11 publications

References 18 publications

Lack of effect of atenolol on the pharmacokinetics of theophylline.

Lack of effect of atenolol on the pharmacokinetics of theophylline.

Integrated in Vitro Analysis for the in Vivo Prediction of Cytochrome P450-Mediated Drug-Drug Interactions

Urinary 6?-hydroxycortisol: a validated test for evaluating drug induction or drug inhibition mediated through CYP3A in humans and in animals

Contact Info

Product

Resources

About