Formation of a thiomethyl metabolite of phenacetin and acetaminophen in dogs and man

Klutch, A.; Levin, Wayne; Chang, Richard L.; Vane, Floie M.; Conney, Allan H.

doi:10.1002/cpt1978243287

Cited by 28 publications

(8 citation statements)

References 3 publications

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“…Using the data of Nahata et al, (1984) a nzoquinineimine. The thioconjugates are very minor significant negative correlation was present between es of paracetamol (Aguilar et al, 1988;Klutch et al, percent increase in AUC (steady state compared with single dose) and age (r2 = -0.56, P = 0.02) after excluding one outlier. This suggests that a reduction in paracetamol clearance with chronic dosing is more likely to occur in younger infants, possibly as a result of 3).…”

Section: Paracetamol Hepatotoxicitymentioning

confidence: 92%

Paracetamol poisoning in children and hepatotoxicity.

Penna

Buchanan

1991

Brit J Clinical Pharma

147

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1. Paracetamol is one of the most common drugs that children accidentally ingest. Unlike the situation in adults, death and hepatotoxicity in children from paracetamol poisoning are exceedingly uncommon events. A review of the literature has revealed only seven deaths and fourteen cases of hepatotoxicity in children, with most of the cases resulting from chronic poisoning and not acute poisoning. 2. Children may be less prone to paracetamol hepatotoxicity because of developmental differences in the drug's metabolism and its pathways of detoxification. In the therapeutic setting of treatment of fever and pain in children, paracetamol is regarded as a drug with a higher therapeutic index, and as such, there seems to be little concern with strict adherence to dosage regimes. 3. Scrutiny of the above paediatric cases associated with chronic paracetamol poisoning suggests that the margin of safety of frequent therapeutic doses of paracetamol in infants and young children to be a lot lower than previously appreciated. This review highlights the need to re‐evaluate the safety of paracetamol in the context of chronic therapy in infants and young children.

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Section: Paracetamol Hepatotoxicitymentioning

confidence: 92%

Paracetamol poisoning in children and hepatotoxicity.

Penna

Buchanan

1991

Brit J Clinical Pharma

147

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“…In keeping with these mechanisms, liver damage and renal failure following paracetamol overdosage can be prevented by early administration of sulphydryl compounds such as N-acetylcysteine (Prescott, Illingworth, Critchley, Stewart, Adam & Proudfoot, 1979). Other minor metabolites of paracetamol include conjugates of 3-methoxy-,3-hydroxy-and 3-thiomethylparacetamol (Andrews, Bond, Burnett, Saunders & Watson, 1976;Klutch, Levin, Chang, Vane & Conney, 1978). Paracetamol metabolism is age-and dosedependent.…”

Section: Metabolismmentioning

confidence: 99%

“…Phenacetin Phenacetin (acetophenetidine) is highly lipid-soluble with limited aqueous solubility, and its oral absorption is highly dependent on formulation factors such as particle size (Prescott, Steel & Ferrier, 1970 (Brodie & Axelrod, 1949;Jagenburg & Toczko, 1964;Buch, Pfleger, Rummel, Ullrich, Hey & Staudinger, 1967;Prescott, 1969;Raaflaub & Dubach, 1969;Nery, 1971;Uehleke, 1973;Smith & Timbrell, 1974;Klutch et al, 1978). There is extensive 'first-pass' metabolism of phenacetin by the small intestinal mucosa and liver, which is inducible by polycyclic hydrocarbons and cigarette smoking (Kuntzman, Pantuck, Kaplan & Conney, 1977).…”

Section: Kineticsmentioning

confidence: 99%

Kinetics and metabolism of paracetamol and phenacetin.

Prescott¹

1980

Brit J Clinical Pharma

393

279

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1 The rate of absorption of oral paracetamol depends on the rate of gastric emptying and is usually rapid and complete. The mean systemic availability is about 757o. 2 Paracetamol is extensively metabolized and the plasma half-life is 1.5-2.5 hours. About 55%o and 3007 of a therapeutic dose is excreted in the urine as glucuronide and sulphate conjugates, respectively, whereas mercapturic acid and cysteine conjugates (representing conversion to a potentially toxic intermediate metabolite) each account for some 4%o of the dose. Paracetamol metabolism is age-and dose-dependent. 3 With hepatotoxic doses, paracetamol metabolism is impaired and the half-life prolonged. Sulphate conjugation is saturated and the proportion excreted as mercapturic acid and cysteine conjugates is increased. 4 The renal clearance of paracetamol depends on urine flow rate by notpH. The renal clearances of' the glucuronide and sulphate conjugates often exceed the glomerular filtration rate and are independent of urine flow and pH. 5 Phenacetin absorption depends on formulation. It is extensively metabolized to paracetamol and minor metabolites are probably responsible for toxicity Paracetamol PARACETAMOL (acetaminophen, N-acetyl-p-aminophenol, 4-hydroxyacetanilide) is a moderately waterand lipid-soluble weak organic acid. It has a pKa value of 9.5 and is therefore largely unionized over the physiological range ofpH.

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“…1975). A thiomethyl metabolite has been observed in work with N-methyl-4-aminobenzene, 2-acetylaminofluorene (Miller 1970), phenacetin, and acetaminophen (Klutch et al 1978). All these metabolic transformations involved a direct substitution onto a ring structure while the caffeine substitution seems to be specific for the 7-methyl group.…”

Section: / --mentioning

confidence: 99%

“…All these metabolic transformations involved a direct substitution onto a ring structure while the caffeine substitution seems to be specific for the 7-methyl group. The postulated mechanisms of formation are said to either involve 3'-phosphoadenosine 5'-phosphosulfate, methionine, and a soluble fraction sulfotransferase (Miller 1970) or a mercapturic acid intermediate (Klutch et al 1978). The resulting sulfide can then be further oxidized to the sulfone or the sulfoxide (Kamei et al 1975).…”

Section: / --mentioning

confidence: 99%

The Pharmacology and Toxicology of Caffeine

Lachance

1982

Journal of Food Safety

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The widespread use of caffeine is most commonly linked to the stimulatory action it has on the central nervous system. Generally, adverse effects include gastrorrhea, insomnia, and diuresis. Tolerance and withdrawal symptoms have been observed and excessive consumption can lead to an anxiety neurosis condition (caffeinism). The actions of caffeine may involve its effects on neurotransmitter turnover and metabolism; its promotion of the cellular messenger, cAMP; its sensitization of the calcium releasing mechanisms of cellular reticulum; or its antagonism of the autacoid, adenosine. Caffeine lethality is rare in man but caffeine poisoning with its gastrointestinal, CNS, and cardiovascular stimulation could especially be hazardous to children. Most of the mutagenicity work has been performed in organisms whose cellular DNA synthesis and repair mechanism vary significantly from those found in man. The work in human cell lines suggests that caffeine‐induced chromosomal breakage, with its lack of chromatid exchange would promote cell lethality, not muta‐genticity. Nothing but circumstantial evidence implicates caffeine as a human carcinogen or teratogen. Involvement of caffeine as a cocarcinogen or a coteratogen (which includes effects on gamete production or fetal development) appears far more likely, but neither has even begun to be truly evaluated. Basic metabolism of caffeine involves the processes of N‐demethylation, hydration, and oxidation; and most likely requires the cytochrome P1‐450 system. Though various metabolites of caffeine are pharmacologically active, the extent of involvement of individual metabolites in the pharmacological or toxicological responses of caffeine in man is still unknown.

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Formation of a thiomethyl metabolite of phenacetin and acetaminophen in dogs and man

Cited by 28 publications

References 3 publications

Paracetamol poisoning in children and hepatotoxicity.

Paracetamol poisoning in children and hepatotoxicity.

Kinetics and metabolism of paracetamol and phenacetin.

The Pharmacology and Toxicology of Caffeine

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