Phenylbutazone and Isoniazid Metabolism in Patients With Liver Disease in Relation to Previous Drug Therapy

Levi, A J; Sherlock, Sheila; Walker, Deward E.

doi:10.1016/s0140-6736(68)92292-7

Cited by 194 publications

(48 citation statements)

References 11 publications

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“…There is a growing literature on the influence of liver disease on drug disposition, with prolongation in the TiA being reported for antipyrine (Branch et al, 1973), phenylbutazone (Levi, Sherlock & Walker, 1968), carbenicillin (Hoffman, Cestero & Bullock, 1970), chloramphenicol (Kunin, Glazko & Finland, 1959) and rifamycin (Acocella, Bonelloa, Garimoldi, Mainardi, Tocini & Nicolis, 1972) The high clearance of (+)-propranolol found in normal subjects, similar to those previously reported , correlated with and was numerically similar to the clearance of ICG. Although one drug is metabolized and the other actively transported to the bile, their hepatic extraction ratios must have been equally high so that the clearance values represented were a slight underestimate of liver blood flow.…”

Section: Discussionsupporting

confidence: 81%

A study of factors influencing drug disposition in chronic liver disease, using the model drug (+)‐propranolol.

Ra¹,

James²,

Read³

1976

Brit J Clinical Pharma

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The pharmacokinetics, following i.v. administration of (+)‐propranolol (40 mg) have been compared to in vitro measurement of protein binding and biochemical parameters of liver function in six normal subjects and twenty patients with stable chronic liver disease. The clearance of (+)‐ propranolol decreased with evidence of increasing severity of impairment of liver function correlating significantly with a fall in serum albumin, a rise in bilirubin and a prolongation in prothrombin index. The clearance of (+)‐propranolol correlated with and was numerically similar to the clearance of indocyanine green in normal subjects and also in patients with chronic liver disease. Protein binding was decreased in chronic liver disease, but this change was not related to changes in plasma proteins. In normal subjects and patients without ascites the volume of distribution increased with decreases in protein binding. Ascites was associated with a further increase in the volume of distribution. The considerable variation in half‐life largely depends on changes in liver blood flow, the degree of protein binding and the plasma protein pool size.

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Section: Discussionsupporting

confidence: 81%

A study of factors influencing drug disposition in chronic liver disease, using the model drug (+)‐propranolol.

Ra¹,

James²,

Read³

1976

Brit J Clinical Pharma

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“…Patients 4 and 7 were excluded from correlation c because the serum albumin concentration had been used in the estimation of the proportion of amylobarbitone protein bound and thus indirectly in the derivation of Ce (ml/min). Levi et al (1968) also found a significant correlation between the concentration of serum albumin and the serum half time of phenylbutazone in patients with chronic liver disease. The degree of bromsulphthalein retention also correlated with the same indices of the rate of amylobarbitone metabolism (a) /3 (h-'), r=-0-79, n=9, P<002; (b) urinary hydroxyamylobarbitone (% per 24 h), r= -0 65, P<0 05; (c) Ce (ml/ min), r= -090, n=9, P<0-005.…”

Section: Discussionmentioning

confidence: 70%

Metabolism of amylobarbitone in patients with chronic liver disease

Mawer

Miller

Turnberg

1972

British J Pharmacology

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Summary A single dose of amylobarbitone (3·23 mg/kg) was given by intravenous injection to each of ten healthy controls and two groups of five patients with chronic liver disease. A curve of serum amylobarbitone concentration against time was prepared for each subject and the proportion of the serum amylobarbitone bound to protein determined. The urinary excretion of the metabolite hydroxyamylobarbitone, ethyl (3 hydroxyisoamyl) barbituric acid was measured. The degree of protein binding of serum amylobarbitone was reduced in the five patients (group I) with abnormally low concentrations of albumin in serum (<3·5 g/100 ml) but was normal in the five patients (group II) with normal serum albumin concentrations (>3·5 g/100 ml). The equation for a double exponential decay was fitted to the concentration/time curves for amylobarbitone free in the serum water. The mean intercepts and rate constants were used to calculate the dimensions of mathematical models based on a two compartment open system. The five patients (group I) who had abnormally low concentrations of albumin in serum showed impairment of amylobarbitone metabolism; the rate constant β(h−1) for the second exponential decay of serum amylobarbitone concentration was reduced (P<0·01), the urinary excretion of hydroxyamylobarbitone was reduced (P<0·001) and the mean serum water clearance (Ce ml/min) representing amylobarbitone elimination by metabolism was reduced. The five patients (group II) who had normal concentrations of albumin in serum showed no impairment of amylobarbitone metabolism. Within the total patient group there were strong and significant positive correlations between the serum albumin concentration and each of the indices of the rate of amylobarbitone metabolism. Both patient groups showed an increase in the first dispositional rate constant α(h−1) and in the clearance (Ct ml/min) representing transfer between central and peripheral compartments. The physiological basis for this observation is uncertain. The clinical response to the single intravenous dose of amylobarbitone was not significantly greater (P=0·11) in the patient group (I) with slow amylobarbitone metabolism than in the patient group (II) with a normal rate of amylobarbitone metabolism.

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“…Such drugs, in addition to phenylbutazone and oxyphenbutazone, include the barbiturates; glutethimide, methylprylone, chloral hydrate, meprobamate, chlordiazepoxide, chlorpromazine, triflupromazine and promazine; the anticonvulsants diphenylhydantoin, methylphenylhydantoin and paramethadione; and tolbutamide (8). Among all these drugs, only phenobarbital has been studied in man in regard to phenylbutazone metabolism; it does indeed induce metabolizing enzymes and shorten phenylbutazone half-life ( 9 ) . T h e physician must be concerned with the possible influences of all these drugs on phenylbutazone metabolism in the human liver and conversely on the possible effect of phenylbutazone on the metabolism of any of these drugs a patient with acute gout might be taking at the same time.…”

Section: Phenylbutazone and Oxyphenbutazonementioning

confidence: 99%

The treatment of gout

Wallace

1972

Arthritis & Rheumatism

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Gout is usually the most treatable of the arthritides. Acute attacks, if caught early enough, can 'be eradicated rapidly and completely. Recurrences can be prevented, and tophi dissolved. The drugs capable of producing these effects are well known. The purpose of this brief review of the therapy of gout is to consider both the basic principles of treatment and some of the newer aspects of the clinical pharmacology of these agents.Traditionally, the treatment of gout is divided into three parts: a) control of the acute episode, b) prevention of subsequent attacks, and c) dissolution of tophaceous deposits by reducing the serum urate level to normal. This subdivision of therapy is still conceptually valid.

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Phenylbutazone and Isoniazid Metabolism in Patients With Liver Disease in Relation to Previous Drug Therapy

Cited by 194 publications

References 11 publications

A study of factors influencing drug disposition in chronic liver disease, using the model drug (+)‐propranolol.

A study of factors influencing drug disposition in chronic liver disease, using the model drug (+)‐propranolol.

Metabolism of amylobarbitone in patients with chronic liver disease

The treatment of gout

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