Determination of bufuralol and its metabolites in plasma by mass fragmentography and by gas chromatography with electron capture detection

Francis, Robert J.; East, P. B.; McLaren, S. J.; Larman, J.

doi:10.1002/bms.1200030606

Cited by 33 publications

(7 citation statements)

References 4 publications

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“…These intermediates are still active: the b-antagonist ED 50 for inhibition of tachycardia in rats are 169, 46/284, and 203 mg/kg for bufuralol (21), the two stereoisomers of 22, and 23, respectively [136,137]. They also have different and long elimination half-lives: biological halflives are 4, 7, and 12 h for bufuralol (21), 22, and 23, respectively [138]. Differential metabolism of the two enantiomers and differences due to genetic polymorphism also occur [139].…”

Section: Active Metabolite-based Soft Drugsmentioning

confidence: 96%

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Retrometabolism‐Based Drug Design and Targeting

Bodor

Buchwald

2010

Burger's Medicinal Chemistry and Drug Discovery

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Retrometabolic drug design (RMDD) approaches are systematic methodologies aimed to design safe compounds with an improved therapeutic index. RMDDs thoroughly integrate structure– activity and structure‐metabolism considerations into the entire design process and incorporate two major concepts aimed to design soft drugs and chemical delivery systems, respectively. Soft drugs (SDs) are new, active therapeutic agents designed to undergo predictable metabolism resulting in inactive metabolites after exerting their desired therapeutic effect(s). Chemical delivery systems (CDSs) are biologically inert molecules that provide enhanced and targeted delivery of an active drug to a particular organ or site through a designed sequential metabolism that involves several steps. Here, we present a comprehensive review including a general overview of the RMDD principles and a large number of specific examples from various pharmacological areas, including many recent developments, to illustrate RMDD concepts. Whenever possible, the rationale for the design as well as the pharmacokinetic and pharmacodynamic properties of the new therapeutic agents are briefly summarized and compared to those of the other compounds used in the same field.

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Section: Active Metabolite-based Soft Drugsmentioning

confidence: 96%

“…7). These intermediates are still active [136,137] and have different (interestingly, longer) elimination halflives [138]. Not only does a differential metabolism of the two enantiomers occur but also differences due to genetic polymorphism are encountered [139].…”

Section: Inactive Metabolite-based Soft Drugsmentioning

confidence: 98%

Retrometabolism‐Based Drug Design and Targeting

Bodor

Buchwald

2010

Burger's Medicinal Chemistry and Drug Discovery

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“…First studies in man have shown that bufuralol has a longer duration of action and a greater potency than propranolol (Kilborn & Turner, 1974;Tschopp et al, 1978). This lipophilic compound is metabolised by the liver and three metabolites of bufuralol have been identified in human plasma: an alcoholic or carbinol derivative (1'-hydroxybufuralol), a phenol derivative (4-hydroxybufuralol) and a ketone derivative (Francis et al, 1976;Balant et al, 1980). The carbinol and the ketone derivatives have been synthesised and shown to possess f3-adrenoceptor blocking activity similar to parent drug (Francis et al, 1976).…”

Section: Defective Hydroxylation Of Bufuralol Associated With Side-efmentioning

confidence: 99%

“…This lipophilic compound is metabolised by the liver and three metabolites of bufuralol have been identified in human plasma: an alcoholic or carbinol derivative (1'-hydroxybufuralol), a phenol derivative (4-hydroxybufuralol) and a ketone derivative (Francis et al, 1976;Balant et al, 1980). The carbinol and the ketone derivatives have been synthesised and shown to possess f3-adrenoceptor blocking activity similar to parent drug (Francis et al, 1976). The main constituent next to the parent compound in human plasma is the active carbinol derivative (Balant et al, 1978a;Balant etal., 1980).…”

Section: Defective Hydroxylation Of Bufuralol Associated With Side-efmentioning

confidence: 99%

Defective hydroxylation of bufuralol associated with side‐effects of the drug in poor metabolisers [letter]

Dayer¹,

Kubli²,

Küpfer³

et al. 1982

Brit J Clinical Pharma

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“…This lipophilic compound is rapidly metabolised by the liver. Studies in animals and man have identified 15 urinary metabolites (3), At least 3 of the urinary metabolites ( Ketonemetabolite to the parent drug (4). In urine, the conjugated phenol-derivative is the main metabolite (20% of the dose) (5,6).…”

Section: Introductionmentioning

confidence: 99%

The genetic controlof bufuralol metabolisminman

Dayer

Balant

Courvoisier

et al. 1982

European Journal of Drug Metabolism and Pharmacokinetics

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Bufuralol (Ro 3 - 4787, Angium) is a non selective beta-adrenoceptor blocking drug with some degree of sympathomimetic action and a longer duration of action than propranolol. Plasma concentrations of bufuralol and 1'-hydroxybufuralol, its main blood derivative which shows similar beta-adrenoceptor blocking properties, were determined in healthy volunteers after a 60 mg oral and a 20 mg intravenous dose. Peak plasma concentrations were higher for the parent drug but due to a longer elimination half-life, the metabolite concentrations became higher after a few hours (bufuralol t 1/2 = 2.7 +/- 0.9 h, metabolite t 1/2 = 6.1 +/- 1.5h). The bioavailability of the tablet tested was 46 +/- 15%. The occurrence of side-effects in a subject with abnormal pharmacokinetics of the drug in this study and in a previous study with this drug suggested the possibility of a pharmacogenetic anomaly. Determination of the plasma metabolic ratio in the family of this subject and in a larger population confirmed that aliphatic hydroxylation of bufuralol is under polymorphic control. Phenotyping of our volunteers with debrisoquine showed the present pharmacogenetic anomaly to be the same as the one reported for debrisoquine alicyclic hydroxylation. The occurrence of side-effects in poor metabolizers as seen with bufuralol illustrates the clinical relevance of the hydroxylation polymorphism. In Switzerland the frequency of poor metabolizers is about 9% as previously reported for caucasian British subjects.

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Determination of bufuralol and its metabolites in plasma by mass fragmentography and by gas chromatography with electron capture detection

Cited by 33 publications

References 4 publications

Retrometabolism‐Based Drug Design and Targeting

Retrometabolism‐Based Drug Design and Targeting

Defective hydroxylation of bufuralol associated with side‐effects of the drug in poor metabolisers [letter]

The genetic controlof bufuralol metabolisminman

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