Possible molecular basis for the pharmacokinetics and pharmacodynamics of three membrane-active drugs: Propranolol, nimodipine and amiodarone+

Herbette, Leo G.; Trumbore, Mark W.; Chester, David W.; Katz, Arnold M.

doi:10.1016/s0022-2828(88)80128-7

Cited by 50 publications

(29 citation statements)

References 12 publications

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“…Such a rank order of behaviour has already been demonstrated for the time needed to antagonize salmeterolinduced relaxation of guinea-pig airway smooth muscle: the rank order is propranolol > ICI 118,551 > timolol > sotalol > atenolol [33,34]. This order is comparable to the rank order of lipophilicity of these drugs [18,[57][58][59][60].…”

Section: Chmentioning

confidence: 80%

“…Propranolol, for example has been clearly demonstrated to partition in membrane bilayers and adopt a specific location, approximately 10 Å into the membrane just under the phospholipid head groups, as detected by neutron diffraction. This property has also been observed for timolol which, unlike propranolol, is not formally charged at physiological pH [18,57,58]. The diffusion microkinetic model would predict that antagonists interacting with membranes in airway smooth muscle tissue pre-relaxed by a beta 2 -adrenoceptor agonist would assert their antagonism at a rate broadly related to their lipophilicities.…”

Section: Chmentioning

confidence: 82%

See 1 more Smart Citation

Why are long-acting beta-adrenoceptor agonists long-acting?

Anderson¹,

Lindén²,

Rabe³

1994

Eur Respir J

221

159

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The extended duration of bronchodilation due to formoterol and salmeterol greatly exceeds that of short acting beta 2-adrenoceptor agonists, such as salbutamol or terbutaline. This extended duration and their capacity to "reassert" airway smooth muscle relaxation in vitro despite repeated washing has prompted considerable debate on the underlying mechanism(s). The comparative pharmacology, and molecular modelling of these drugs and of the beta 2-adrenoceptor and its ligand binding core have cast doubt on the exosite/exoceptor model previously proposed to explain the behaviour of salmeterol. We present evidence supporting a unifying hypothesis that the duration of action both of formoterol and salmeterol is determined principally by their physicochemical interactions with membrane lipid bilayers (plasmalemma diffusion microkinetic model), rather than putative distinct exosite/exoceptor binding sites in or near the beta 2-adrenoceptor. This model provides a clearer understanding of the pharmacological profile of these drugs (rate of onset, duration, "reassertion", interaction with hydrophilic and hydrophobic beta 2-adrenoceptor antagonists), and explains why in human airway smooth muscle in vitro a true relaxation-concentration response may not exist for salmeterol.

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Section: Chmentioning

confidence: 80%

Section: Chmentioning

confidence: 82%

Why are long-acting beta-adrenoceptor agonists long-acting?

Anderson¹,

Lindén²,

Rabe³

1994

Eur Respir J

221

159

View full text Add to dashboard Cite

show abstract

“…In S. cerevisiae , toxic levels of amiodarone trigger a transient membrane hyperpolarization, likely through its ability to intercalate into the lipid bilayer (Herbette et al, 1988) altering lipid fluidity (Rosa et al, 2000), which is followed by depolarization, coincident with influx of Ca 2 + and H + that can overwhelm cellular homeostasis and lead to cell death (Maresova et al, 2009). Amiodarone has been shown to have potent fungicidal activity against not only S. cerevisiae , but also for species of Cryptococcus , Candida , Fusarium , and Aspergillus (Courchesne, 2002).…”

Section: Rafts and Cell Death In Yeastmentioning

confidence: 99%

Lipid raft involvement in yeast cell growth and death

Mollinedo¹

2012

Front. Oncol.

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The notion that cellular membranes contain distinct microdomains, acting as scaffolds for signal transduction processes, has gained considerable momentum. In particular, a class of such domains that is rich in sphingolipids and cholesterol, termed as lipid rafts, is thought to compartmentalize the plasma membrane, and to have important roles in survival and cell death signaling in mammalian cells. Likewise, yeast lipid rafts are membrane domains enriched in sphingolipids and ergosterol, the yeast counterpart of mammalian cholesterol. Sterol-rich membrane domains have been identified in several fungal species, including the budding yeast Saccharomyces cerevisiae, the fission yeast Schizosaccharomyces pombe as well as the pathogens Candida albicans and Cryptococcus neoformans. Yeast rafts have been mainly involved in membrane trafficking, but increasing evidence implicates rafts in a wide range of additional cellular processes. Yeast lipid rafts house biologically important proteins involved in the proper function of yeast, such as proteins that control Na+, K+, and pH homeostasis, which influence many cellular processes, including cell growth and death. Membrane raft constituents affect drug susceptibility, and drugs interacting with sterols alter raft composition and membrane integrity, leading to yeast cell death. Because of the genetic tractability of yeast, analysis of yeast rafts could be an excellent model to approach unanswered questions of mammalian raft biology, and to understand the role of lipid rafts in the regulation of cell death and survival in human cells. A better insight in raft biology might lead to envisage new raft-mediated approaches to the treatment of human diseases where regulation of cell death and survival is critical, such as cancer and neurodegenerative diseases.

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“…Such interactions could involve the head groups of membrane phospholipids [59] and/or their hydrocarbon chains (so that the ligands become completely embedded within the lipid bilayer) [60,61]. Such ligands could be especially prone to undergo rebinding to membrane-associated receptors if they are able to access their active site by lateral diffusion between the receptor's membrane-spanning a-helical domains [62].…”

Section: What Features Promote Local Rebinding and How To Equate Thismentioning

confidence: 99%