Drug conjugation in clinical toxicology

Prescott, L. F.

doi:10.1042/bst0120096

Cited by 12 publications

(8 citation statements)

References 24 publications

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“…There is no decrease in this fraction after overdosage and glucuronide conjugation probably only becomes saturated in large overdoses. 9 Comparison of pharmacokinetic parameters of the glucuronide metabolite showed no significant difference in AUC(0-•) and Tmax between the two formulations. However, in the Panadol Extend arm there was a moderate but significant lower Cmax.…”

Section: Discussionmentioning

confidence: 88%

“…Glucuronide conjugation is the major route of paracetamol metabolism accounting for about 60% of metabolism at a therapeutic dose. There is no decrease in this fraction after overdosage and glucuronide conjugation probably only becomes saturated in large overdoses 9 . Comparison of pharmacokinetic parameters of the glucuronide metabolite showed no significant difference in AUC (0–∞) and Tmax between the two formulations.…”

Section: Discussionmentioning

confidence: 91%

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The comparative pharmacokinetics of modified‐release and immediate‐release paracetamol in a simulated overdose model

Chiew

Day²,

Salonikas³

et al. 2010

Emerg Medicine Australasia

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 91%

The comparative pharmacokinetics of modified‐release and immediate‐release paracetamol in a simulated overdose model

Chiew

Day²,

Salonikas³

et al. 2010

Emerg Medicine Australasia

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“…(f) Incorporation during de novo synthesis of purines and heme (44,45). (g) Participation in conjugation reactions with carboxylic acids (46)(47)(48). Glycine N-acyltransferase, which mediates production of acylglycine from acyl-coenzyme A (CoA) and glycine, has been identified in both kidney and liver (47,48).…”

Section: Discussionmentioning

confidence: 99%

Cytoprotective effects of glycine and glutathione against hypoxic injury to renal tubules.

Weinberg¹,

Davis²,

Abarzua³

et al. 1987

J. Clin. Invest.

260

141

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Roles for both the tripeptide, GSH, and individual amino acids in modifying the cellular response to oxygen deprivation-induced injury have been suggested by prior work in kidney and other tissues, but the precise interrelationships have not been clearly defined. We have studied the effects of GSH, its component amino acids, and related compounds on the behavior of isolated renal proximal tubules in a well characterized model of hypoxic injury in vitro. GSH, the combination of cysteine, glutamate, and glycine and glycine alone, when present in the medium during 30 min hypoxia, a duration sufficient to produce extensive irreversible injury in untreated tubules, were protective. Significant effects were detected at 0.25 mM concentrations of the reagents, and protection was nearly complete at concentrations of 1 mM and above. Glutamate and cysteine alone were not protective. The exogenous GSH added to the tubule suspensions was rapidly degraded to its component amino acids. Treatment of tubules with GSH or cysteine, but not glycine, increased intracellular GSH levels. Oxidized GSH was protective. Serine, N-(2-mercaptopropionyl)-glycine, and a panel of agents known to modify injury produced by reactive oxygen metabolites were without benefit. These observations identify a novel and potent action of glycine to modify the course of hypoxic renal tubular cell injury. This effect is independent of changes in cellular GSH metabolism and appears to be unrelated to alterations of cell thiols or reactive oxygen metabolites. Further elucidation of its mechanism may provide insight into both the basic pathophysiology of oxygen deprivation-induced cell injury and a practical way to ameliorate it.

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“…Most glucuronosyltransferases enzymes (UGTs) can metabolize paracetamol and unlike sulphotransferase enzymes, glucuronidation is a non‐saturable pathway . A study of repeated paracetamol dosing at 4 g, 6 g and 8 g daily over 3 days in 24 healthy young men and women of normal weight has demonstrated a higher concentration of the glucuronide conjugate and a lower concentration of sulphate and thiol conjugates than was anticipated from single dose data, suggestive of time‐dependent changes in paracetamol metabolism .…”

Section: The Evolution Of Paracetamol In Clinical Carementioning

confidence: 97%

Can paracetamol (acetaminophen) be administered to patients with liver impairment?

Hayward

Powell

Irvine

et al. 2015

Brit J Clinical Pharma

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Although 60 years have passed since it became widely available on the therapeutic market, paracetamol dosage in patients with liver disease remains a controversial subject. Fulminant hepatic failure has been a well documented consequence of paracetamol overdose since its introduction, while short and long term use have both been associated with elevation of liver transaminases, a surrogate marker for acute liver injury. From these reports it has been assumed that paracetamol use should be restricted or the dosage reduced in patients with chronic liver disease. We review the factors that have been purported to increase risk of hepatocellular injury from paracetamol and the pharmacokinetic alterations in different pathologies of chronic liver disease which may affect this risk. We postulate that inadvertent under‐dosing may result in concentrations too low to enable efficacy. Specific research to improve the evidence base for prescribing paracetamol in patients with different aetiologies of chronic liver disease is needed.

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Drug conjugation in clinical toxicology

Cited by 12 publications

References 24 publications

The comparative pharmacokinetics of modified‐release and immediate‐release paracetamol in a simulated overdose model

The comparative pharmacokinetics of modified‐release and immediate‐release paracetamol in a simulated overdose model

Cytoprotective effects of glycine and glutathione against hypoxic injury to renal tubules.

Can paracetamol (acetaminophen) be administered to patients with liver impairment?

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