Paracetamol disposition in normal subjects and in patients treated with antiepileptic drugs.

Perucca, Emilio; Richens, A.

doi:10.1111/j.1365-2125.1979.tb00922.x

Cited by 80 publications

(32 citation statements)

References 29 publications

(40 reference statements)

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“…In addition, paracetamol has been shown to have lower bioavailability in epilectic patients receiving enzyme inducing anticonvulsants (162), including phenytoin and fosphenytoin. On the other hand, paracetamol enhances the urinary elimination of lamotrigine (67).…”

Section: Drug Interactionsmentioning

confidence: 99%

Paracetamol: New Vistas of an Old Drug

et al. 2006

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Paracetamol (acetaminophen) is one of the most popular and widely used drugs for the treatment of pain and fever. It occupies a unique position among analgesic drugs. Unlike NSAIDs it is almost unanimously considered to have no antiinflammatory activity and does not produce gastrointestinal damage or untoward cardiorenal effects. Unlike opiates it is almost ineffective in intense pain and has no depressant effect on respiration. Although paracetamol has been used clinically for more than a century, its mode of action has been a mystery until about one year ago, when two independent groups (Zygmunt and colleagues and Bertolini and colleagues) produced experimental data unequivocally demonstrating that the analgesic effect of paracetamol is due to the indirect activation of cannabinoid CB 1 receptors. In brain and spinal cord, paracetamol, following deacetylation to its primary amine (p-aminophenol), is conjugated with arachidonic acid to form N-arachidonoylphenolamine, a compound already known (AM404) as an endogenous cannabinoid. The involved enzyme is fatty acid amide hydrolase. N-arachidonoylphenolamine is an agonist at TRPV1 receptors and an inhibitor of cellular anandamide uptake, which leads to increased levels of endogenous cannabinoids; moreover, it inhibits cyclooxygenases in the brain, albeit at concentrations that are probably not attainable with analgesic doses of paracetamol. CB 1 receptor antagonist, at a dose level that completely prevents the analgesic activity of a selective CB 1 receptor agonist, completely prevents the analgesic ac- 250CNS Drug Reviews Vol. 12, No. 3-4, pp. 250-275 © 2006 tivity of paracetamol. Thus, paracetamol acts as a pro-drug, the active one being a cannabinoid. These findings finally explain the mechanism of action of paracetamol and the peculiarity of its effects, including the behavioral ones. Curiously, just when the first CB 1 agonists are being introduced for pain treatment, it comes out that an indirect cannabinomimetic had been extensively used (and sometimes overused) for more than a century.

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Section: Drug Interactionsmentioning

confidence: 99%

Paracetamol: New Vistas of an Old Drug

et al. 2006

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“…Paracetamol clearances were not calculated because its significant and variable first-pass metabolism would invalidate comparisons between the groups (Perucca & Richens, 1979). Student's t-test was used for statistical comparisons of mean data.…”

Section: Methodsmentioning

confidence: 99%

“…These differences were due to increased glucuronide conjugation of paracetamol in the patients since the AUCo.gh for the sulphate conjugate was similar in both groups while the initial glucuronide concentrations and AUCo48h were higher in the patients. The ratio of the AUCs of Perucca & Richens (1979) demonstrated reduced oral bioavailability of paracetamol which they attributed to increased first-pass metabolism in six epileptics compared with six normal subjects. The mean total body clearance and elimination rate were higher in the former group but the differences were not significant.…”

Section: Paracetamol and Metabolites In Plasmamentioning

confidence: 99%

Effects of microsomal enzyme induction on paracetamol metabolism in man.

Prescott¹,

Critchley²,

Balali-Mood³

et al. 1981

Brit J Clinical Pharma

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1 The metabolism of paracetamol after a single oral dose of 20 mg/kg was compared in fifteen patients with microsomal enzyme induction taking anticonvulsants or rifampicin and twelve healthy volunteers. 2 Induction was confirmed by measurement of the plasma antipyrine half‐ life (mean 6.4 h in the patients compared with 12.8 h in the volunteers). 3 The glucuronide conjugation of paracetamol was enhanced in the induced patients as shown by lower plasma paracetamol concentrations, a shorter paracetamol half‐life, higher paracetamol glucuronide concentrations and an increased ratio of the area under the plasma concentration time curves of the glucuronide to the unchanged drug. There were no significant differences in sulphate conjugation. 4 There was a corresponding change in the pattern of urinary metabolite excretion. The induced patients excreted significantly less unchanged drug and sulphate conjugate and more glucuronide conjugate than the healthy volunteers. 5 The urinary excretion of the mercapturic acid and cysteine conjugated of paracetamol was the same in both groups. 6 Conversion of paracetamol to its potentially hepatotoxic metabolite does not seem to be increased in patients induced with anticonvulsants or rifampicin. There would seem to be no contraindication to the use of these drugs in combination.

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“…Since paracetamol is oxidised to a hepatotoxic intermediate metabolite N-acetyl p-benzoquinoneimine (Corcoran et al, 1980;Meredith & Goulding, 1980), interactions with drugs that induce hepatic mono-oxygenases (Mitchell etal., 1983;Perucca & Richens, 1979;Prescott et al, 1981) and those that inhibit them (Mitchell et al, 1984;Sanchez-Martinez et al, 1985) are of interest.…”

Section: Introductionmentioning

confidence: 99%

The effect of propranolol on paracetamol metabolism in man.

Baraka

Truman

Ford

et al. 1990

Brit J Clinical Pharma

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Ten healthy volunteers were treated for 4 days with 160 mg propranolol HCl and placebo in random order. At the end of each treatment salivary antipyrine kinetics and the plasma kinetics and urinary excretion of paracetamol and its major metabolites were measured following a 1500 mg oral dose. Propranolol prolonged the half-life of antipyrine by 11 ± 5% (mean ± s.e. mean) and lowered its clearance by 14 ± 3% (P < 0.05). Propranolol increased the half-life of paracetamol by 25 ± 12% (P < 0.05) and lowered its clearance by 14 ± 3% (P < 0.05). Propranolol decreased the partial clearance of paracetamol to its cysteine and mercapturate derivatives by 16 ± 3% (P < 0.05) and 32 ± 7% (P < 0.05), respectively. The partial clearance to the glucuronide conjugate was decreased by 27 ± 6% (P < 0.05), whereas that to sulphate was not changed significantly. Propranolol inhibits paracetamol metabolism predominantly through inhibition of the oxidation and glucuronidation pathways.Keywords drug metabolism drug interaction propranolol paracetamol antipyrine

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Paracetamol disposition in normal subjects and in patients treated with antiepileptic drugs.

Cited by 80 publications

References 29 publications

Paracetamol: New Vistas of an Old Drug

Paracetamol: New Vistas of an Old Drug

Effects of microsomal enzyme induction on paracetamol metabolism in man.

The effect of propranolol on paracetamol metabolism in man.

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