Glucuronidation of paracetamol, morphine and 1-naphthol in the rat intestinal loop

Josting, Dorothee; Winne, D.; Bock, Karl Walter

doi:10.1016/0006-2952(76)90399-3

Cited by 43 publications

(8 citation statements)

References 7 publications

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“…Only 2–5% of the ingested dose of APAP is excreted unchanged in the urine [143,144,145]. The major metabolites of APAP are the glucuronide and sulfate conjugates, while a minor fraction is converted in the liver by CYP2E1 to a highly reactive toxic electrophilic arylating metabolite, N -acetyl- p -benzoquinoneimine (NAPQI).…”

Section: Direct Hepatocyte Toxicitymentioning

confidence: 99%

Drug-Induced Liver Injury: Cascade of Events Leading to Cell Death, Apoptosis or Necrosis

Iorga

Dara

Kaplowitz

2017

IJMS

228

133

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Drug-induced liver injury (DILI) can broadly be divided into predictable and dose dependent such as acetaminophen (APAP) and unpredictable or idiosyncratic DILI (IDILI). Liver injury from drug hepatotoxicity (whether idiosyncratic or predictable) results in hepatocyte cell death and inflammation. The cascade of events leading to DILI and the cell death subroutine (apoptosis or necrosis) of the cell depend largely on the culprit drug. Direct toxins to hepatocytes likely induce oxidative organelle stress (such as endoplasmic reticulum (ER) and mitochondrial stress) leading to necrosis or apoptosis, while cell death in idiosyncratic DILI (IDILI) is usually the result of engagement of the innate and adaptive immune system (likely apoptotic), involving death receptors (DR). Here, we review the hepatocyte cell death pathways both in direct hepatotoxicity such as in APAP DILI as well as in IDILI. We examine the known signaling pathways in APAP toxicity, a model of necrotic liver cell death. We also explore what is known about the genetic basis of IDILI and the molecular pathways leading to immune activation and how these events can trigger hepatotoxicity and cell death.

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Section: Direct Hepatocyte Toxicitymentioning

confidence: 99%

Drug-Induced Liver Injury: Cascade of Events Leading to Cell Death, Apoptosis or Necrosis

Iorga

Dara

Kaplowitz

2017

IJMS

228

133

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“…Paracetamol is extensively metabolized and only 2-5Wo of a therapeutic dose is excreted unchanged in the urine. Although biotransformation occurs predominately in the liver, there may be some metabolism of the drug in the gut and kidney (Josting, Winne & Bock, 1976;Jones, Sundby, Ormstad & Orrenius, 1979;Mitchell, McMurtry, Statham & Nelson, 1977).…”

Section: Metabolismmentioning

confidence: 99%

“…Absorption from the gastrointestinal tract is by passive transport (Bagnall, Kelleher, Walker & Losowsky, 1979) and there is only minor metabolism of the drug by the gastrointestinal mucosa in the rat (Josting, Winne & Bock, 1976). In man, paracetamol absorption is negligible from the stomach but very rapid from the small intestine and the rate of absorption therefore depends on the rate of gastric emptying .…”

Section: Absorptionmentioning

confidence: 99%

“…Although biotransformation occurs predominately in the liver, there may be some metabolism of the drug in the gut and kidney (Josting, Winne & Bock, 1976;Jones, Sundby, Ormstad & Orrenius, 1979;Mitchell, McMurtry, Statham & Nelson, 1977 (Mitchell, Jollow, Potter, Davis, Gillette & Brodie, 1973;Mitchell, Thorgeirsson, Potter, Jollow & Keiser, 1974). Paracetamol causes acute renal tubular necrosis by a similar mechanism and its toxicity is dependent on microsomal enzyme activity and glutathione availability (Mitchell et al, 1977).…”

Section: Metabolismmentioning

confidence: 99%

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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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“…In a later study using the same technique, Wollenberg & Rummel (1984) found that the sulphoconjugate of some phenolic drugs were transferred mainly to the lumen, whereas other just like 1-naphthol sulphate accumulated in the vascular perfusion medium. In vivo studies (Barr & Riegelman 1970;Bock & Winne 1975;Josting et al 1976;Lasker & Rickert 1978) have shown that intestinally formed conjugates are released into the lumen as well as into the blood. The 1umen:blood side distribution ratio may depend on the species, the drug and the experimental conditions.…”

Section: /'mentioning

confidence: 99%

Drug Metabolism and Metabolite Transport in the Small and Large Intestine: Experiments with 1‐Naphthol and Phenolphthalein by Luminal and Contraluminal Administration in the Isolated Guinea Pig Mucosa

Sund

Lauterbach

1986

Acta Pharmacologica et Toxicologica

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The metabolism and metabolite transport of the monophenol 1‐naphthol (I) and the diphenol phenolphthalein (II) have been studied in a symmetrical setup of the isolated jejunal and colonic mucosa from the guinea pig (Lauterbach 1977). In both tissues, the main metabolites of I were its sulphoconjugate and glucuronide, but the rate of metabolism, relative proportion of the metabolites and their distribution pattern varied with tissue and drug administration side in the following manner: By luminal administration (50 nmol/ml) in the jejunum, the metabolism was nearly complete within 45 min., more sulphate (1.5–3x) than glucuronide was formed, and both metabolites were predominantly transferred back to the lumen. By blood‐side administration, the metabolism was less complete due to a significant decrease of the sulphated fraction. In concequence, more glucuronide (1.5–3x) than sulphate was formed. Moreover, the efflux pattern of the metabolites changed completely; the greater part of the glucuronide fraction now being conveyed to the blood side, whereas the sulphate tended to distribute in a 1:1 fashion on the lumen and blood side. The colonic mucosa behaved in a dissimilar way, since neither I metabolism nor metabolite efflux pattern in this tissue was influenced significantly by drug administration side. More sulphate (1.5–3x) than glucuronide was formed by both routes, and the metabolite distribution was similar to that observed by blood side administration in the jejunum. The changes described above were associated with changes in tissue accumulation of free I and metabolites; accumulation of I by luminal administration in jejunum was insignificant and that of the metabolites small. The main change caused by a higher concentration of I (130 nmol/ml) was a decrease in the sulphated fraction in the colon. II was metabolized at a slower rate than I, and a significant tissue accumulation of free II was observed in all instances. The monoglucuronide was the main metabolite. Only minor amounts of II monosulphate were formed, making its distribution pattern difficult to ascertain. The distribution of II monoglucuronide on the other hand was generally similar to that described for its I analogue.

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Glucuronidation of paracetamol, morphine and 1-naphthol in the rat intestinal loop

Cited by 43 publications

References 7 publications

Drug-Induced Liver Injury: Cascade of Events Leading to Cell Death, Apoptosis or Necrosis

Drug-Induced Liver Injury: Cascade of Events Leading to Cell Death, Apoptosis or Necrosis

Kinetics and metabolism of paracetamol and phenacetin.

Drug Metabolism and Metabolite Transport in the Small and Large Intestine: Experiments with 1‐Naphthol and Phenolphthalein by Luminal and Contraluminal Administration in the Isolated Guinea Pig Mucosa

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