Kinetics and Biotransformation of Adrenergic Inhibitors

Smith, A. J.; Tucker, GT

doi:10.1007/978-3-642-67584-3_12

Cited by 14 publications

(8 citation statements)

References 235 publications

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“…Other known routes of propranolol metabolism are N-dealkylation followed by side-chain deamination and glucuronidation of parent drug (Smith & Tucker, 1980). As with the 4-hydroxylation of debrisoquine N-dealkylation reactions are catalysed by the mixed-function oxidases.…”

Section: Resultsmentioning

confidence: 99%

The relationship between debrisoquine oxidation phenotype and the pharmacokinetics and pharmacodynamics of propranolol.

Lennard¹,

Jackson²,

Freestone³

et al. 1984

Brit J Clinical Pharma

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1 The pharmacokinetics and pharmacodynamics of propranolol (80 mg by mouth) were studied in seven extensive and four poor metabolisers of debrisoquine. 2 Evidence for impairment of the 4'-hydroxylation of propranolol was found in poor metabolisers. However, no significant difference was detected in the oral clearance of unchanged drug between the two groups of debrisoquine oxidation phenotypes. 3 Poor metabolisers of debrisoquine did not experience more intense or more prolonged ,8-adrenoceptor blockade than extensive metabolisers of debrisoquine.

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Section: Resultsmentioning

confidence: 99%

The relationship between debrisoquine oxidation phenotype and the pharmacokinetics and pharmacodynamics of propranolol.

Lennard¹,

Jackson²,

Freestone³

et al. 1984

Brit J Clinical Pharma

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“…The control group of arthritic rats received injections of saline three times daily. All dosages were based on levels used in previous studies with Sprague-Dawley rats (1,(8)(9)(10)(11)(12)(13)(14)(15)(16)(17).…”

Section: Methodsmentioning

confidence: 99%

Beta 2-adrenergic mechanisms in experimental arthritis.

Levine

Coderre

Helms

et al. 1988

Proc. Natl. Acad. Sci. U.S.A.

117

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We have studied (i) the contribution of specific adrenergic receptors to the proinflammatory effects of the sympathetic nervous system in experimental arthritis and (it) the phases of the disease during which the sympathetic nervous system influences joint injury. Severity of joint injury was measured radiographically 28 days after induction of adjuvant arthritis in control rats and in rats treated with a variety of sympatholytic agents at various times during the course of the disease. Rats treated with a nonspecific catecholamine depletor (reserpine) or a P-adrenergic receptor antagonist (propranolol) had a delayed onset and significantly less severe joint injury than saline-treated controls when treatment began prior to injection of the adjuvant and continued to day 28 after the injection. When administered over the same treatment period, neither nonselective (phenoxybenzamine) nor selective [prazosin (ai) and yohimbine (a%)] a-adrenergic receptor antagonists affected the onset or severity ofjoint injury. Metoprolol, a (31 antagonist, was also without effect. In contrast, two P2 antagonists (butoxamine and ICI 118,551) significantly retarded disease onset and reduced the severity of joint injury. When reserpine or butoxamine treatment was initiated after the onset of clinically apparent arthritis, it was still possible to favorably influence the course of the disease. These data indicate an important contribution of the P32-adrenergic receptor to joint injury in experimental arthritis.

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“…Although some of the ~-adrenoceptor antagonists including atenolol, nadolol, practolol and sotalol are excreted unchanged in the urine (table II), the majority are subject to highly variable first-pass oxidative metabolism (Smith & Tucker 1980). Labetalol is conjugated (McNeil & Louis 1984) in its first-pass metabolism, acebutolol is acetylated, although this is not under genetic control (Gulaid et al 1978), and pindolol is conjugated and oxidised (Smith & Tucker 1980).…”

Section: Metabolismmentioning

confidence: 99%

Clinical Pharmacokinetics of ??-Adrenoceptor Antagonists

Riddell¹,

Harron²,

Shanks³

1987

Clinical Pharmacokinetics

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The beta-adrenoceptor antagonists have been widely used clinically for over 20 years and their pharmacokinetics have been more thoroughly investigated than any other group of drugs. Their various lipid solubilities are associated with differences in absorption, distribution and excretion. All are adequately absorbed, and some like atenolol, sotalol and nadolol which are poorly lipid-soluble are excreted unchanged in the urine, accumulating in renal failure but cleared normally in liver disease. The more lipid-soluble drugs are subject to variable metabolism in the liver, which may be influenced by age, phenotype, environment, disease and other drugs, leading to more variable plasma concentrations. Their clearance is reduced in liver disease but is generally unchanged in renal dysfunction. All the beta-adrenoceptor antagonists reduce cardiac output and this may reduce hepatic clearance of highly extracted drugs. In addition, the metabolised drugs compete with other drugs for enzymatic biotransformation and the potential for interaction is great, but because of the high therapeutic index of beta-adrenoceptor antagonists, any unexpected clinical effects are more likely to be due to changes in the kinetics of the other drug. Because satisfactory plasma concentration effect relationships have been difficult to establish for most clinical indications, and little dose-related toxicity is seen, plasma beta-adrenoceptor antagonist concentration measurement is usually unnecessary. The investigation of the clinical pharmacokinetics of the beta-adrenoceptor antagonists has added greatly to our theoretical and practical knowledge of pharmacokinetics and made some contribution to their better clinical use.

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Kinetics and Biotransformation of Adrenergic Inhibitors

Cited by 14 publications

References 235 publications

The relationship between debrisoquine oxidation phenotype and the pharmacokinetics and pharmacodynamics of propranolol.

The relationship between debrisoquine oxidation phenotype and the pharmacokinetics and pharmacodynamics of propranolol.

Beta 2-adrenergic mechanisms in experimental arthritis.

Clinical Pharmacokinetics of ??-Adrenoceptor Antagonists

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