Studies on the fate of naproxen. II. Metabolic fate in various animals and man.

Sugawara, Yoichi; Fujihara, Michio; Miura, Yuji; Hayashida, Kokichi; Takahashi, Tadao

doi:10.1248/cpb.26.3312

Cited by 30 publications

(25 citation statements)

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“…Metabolites of ibuprofen and (S)-naproxen were reported to be excreted in urine, which suggested that the kidneys are the main excretion route (Sugawara et al, 1978;Shirley et al, 1994;Kepp et al, 1997). Furthermore, we used r-PXB mice as a control model in consideration of species differences between humans and rats in this study.…”

Section: Discussionmentioning

confidence: 99%

“…dmd.aspetjournals.org acyl glucuronide, which were reported to be mainly excreted in the urine of humans (Fig. 2) (Sugawara et al, 1978). (S)-Naproxen was also excreted at negligible levels.…”

Section: Cumulative Urinary Excretion Of Six Metabolites Of Ibuprofenmentioning

confidence: 93%

“…Human data (mean Ϯ S.D., n ϭ 3) after oral administration (200 mg/person) are from Sugawara et al (1978). The amounts of acyl glucuronide formed were determined by hydrolysis with ␤-glucuronidase.…”

Section: Cumulative Urinary Excretion Of Four Metabolites Of (S)-naprmentioning

confidence: 99%

“…The amounts of acyl glucuronide formed were determined by hydrolysis with ␤-glucuronidase. The amount of sulfate of desmethyl naproxen was determined by hydrolysis with 2 N HCl (Sugawara et al, 1978). Data on metabolites of h-PXB mice, r-PXB mice, and rats after oral administration (10 mg/kg) are means Ϯ S.D.…”

Section: Cumulative Urinary Excretion Of Four Metabolites Of (S)-naprmentioning

confidence: 99%

“…These metabolites are mainly excreted in urine. Furthermore, species differences in the metabolism of ibuprofen and (S)-naproxen between rats and humans have also been reported (Mills et al, 1973;Sugawara et al, 1978).…”

Section: Introductionmentioning

confidence: 98%

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Predictability of Metabolism of Ibuprofen and Naproxen Using Chimeric Mice with Human Hepatocytes

et al. 2012

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ABSTRACT:Prediction of human drug metabolism is important for drug development. Recently, the number of new drug candidates metabolized by not only cytochrome P450 (P450) but also non-P450 has been increasing. It is necessary to consider species differences in drug metabolism between humans and experimental animals. We examined species differences of drug metabolism, especially between humans and rats, for ibuprofen and (S)-naproxen as nonsteroidal anti-inflammatory drugs, which are metabolized by P450 and UDP-glucuronosyltransferase, sulfotransferase, and amino acid N-acyltransferase for taurine conjugation in liver, using human chimeric mice (h-PXB mice) repopulated with human hepatocytes and rat chimeric mice (r-PXB mice) transplanted with rat hepatocytes. We performed the direct comparison of excretory metabolites in urine between h-PXB mice and reported data for humans as well as between r-PXB mice and rats after administration of ibuprofen and (S)-naproxen. Good agreement for urinary metabolites (percentage of dose) was observed not only between humans and h-PXB mice but also between rats and r-PXB mice. Therefore, the metabolic profiles in humans and rats reflected those in h-PXB mice and r-PXB mice. Our results indicated that h-PXB mice should be helpful for predicting the quantitative metabolic profiles of drugs mediated by P450 and non-P450 in liver, and r-PXB mice should be helpful for evaluation of species differences in these metabolic enzymes.

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Section: Discussionmentioning

confidence: 99%

Section: Cumulative Urinary Excretion Of Six Metabolites Of Ibuprofenmentioning

confidence: 93%

Section: Cumulative Urinary Excretion Of Four Metabolites Of (S)-naprmentioning

confidence: 99%

Section: Cumulative Urinary Excretion Of Four Metabolites Of (S)-naprmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

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Predictability of Metabolism of Ibuprofen and Naproxen Using Chimeric Mice with Human Hepatocytes

et al. 2012

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Chimeric mice transplanted with human hepatocytes as a model for prediction of human drug metabolism and pharmacokinetics

Sanoh

Ohta

2013

Biopharm & Drug Disp

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Preclinical studies in animal models are used routinely during drug development, but species differences of pharmacokinetics (PK) between animals and humans have to be taken into account in interpreting the results. Human hepatocytes are also widely used to examine metabolic activities mediated by cytochrome P450 (P450) and other enzymes, but such in vitro metabolic studies also have limitations. Recently, chimeric mice with humanized liver (h-chimeric mice), generated by transplantation of human donor hepatocytes, have been developed as a model for the prediction of metabolism and PK in humans, using both in vitro and in vivo approaches. The expression of human-specific metabolic enzymes and metabolic activities was confirmed in humanized liver of h-chimeric mice with high replacement ratios, and several reports indicate that the profiles of P450 and non-P450 metabolism in these mice adequately reflect those in humans. Further, the combined use of h-chimeric mice and r-chimeric mice, in which endogenous hepatocytes are replaced with rat hepatocytes, is a promising approach for evaluation of species differences in drug metabolism. Recent work has shown that data obtained in h-chimeric mice enable the semi-quantitative prediction of not only metabolites, but also PK parameters, such as hepatic clearance, of drug candidates in humans, although some limitations remain because of differences in the metabolic activities, hepatic blood flow and liver structure between humans and mice. In addition, fresh h-hepatocytes can be isolated reproducibly from h-chimeric mice for metabolic studies.

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Pharmacokinetics of naproxen, its metabolite O‐desmethylnaproxen, and their acyl glucuronides in humans

Vree

Biggelaar-Martea

Wissen

et al. 1993

Biopharm & Drug Disp

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The aim of this investigation was to assess the pharmacokinetics of naproxen in 10 human subjects after an oral dose of 500 mg using a direct HPLC analysis of the acyl glucuronide conjugates of naproxen and its metabolite O-desmethylnaproxen. The mean t1/2 of naproxen in 9 subjects was 24.7 +/- 6.4 h (range 16 to 36 h). The t1/2 of 7.4 as found in subject number 10 must, therefore, be regarded as an extraordinary case (p < 0.0153). Naproxen acyl glucuronide accounts for 50.8 +/- 7.32 per cent of the dose, its isomerized conjugate isoglucuronide for 6.5 +/- 2.0 per cent, O-desmethylnaproxen acyl glucuronide for 14.3 +/- 3.4 per cent, and its isoglucuronide for 5.5 +/- 1.3 per cent (n = 10; 100 h collection period). Naproxen and O-desmethylnaproxen are excreted in negligible amounts (< 1 per cent). Even though urine pH of the subjects was kept acid (range pH 5.0-5.5) in order to stabilize the acyl glucuronides, isomerization takes place in blood when the acyl glucuronide is released from the liver for excretion by the kidney. Binding to plasma proteins was measured as 98 per cent and 100 per cent, respectively for the unconjugated compounds naproxen and O-desmethylnaproxen. Binding of the acyl glucuronides was less, being 92 per cent; for naproxen acyl glucuronide, 66 per cent for naproxen isoglucuronide, 72 per cent for O-desmethylnaproxen acyl glucuronide and 42 per cent for O-desmethylnaproxen isoglucuronide.

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Studies on the fate of naproxen. II. Metabolic fate in various animals and man.

Cited by 30 publications

References 0 publications

Predictability of Metabolism of Ibuprofen and Naproxen Using Chimeric Mice with Human Hepatocytes

Predictability of Metabolism of Ibuprofen and Naproxen Using Chimeric Mice with Human Hepatocytes

Chimeric mice transplanted with human hepatocytes as a model for prediction of human drug metabolism and pharmacokinetics

Pharmacokinetics of naproxen, its metabolite O‐desmethylnaproxen, and their acyl glucuronides in humans

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