Selective Downregulation of Hepatic Cytochrome P450 Expression and Activity in a Rat Model of Inflammatory Pain

Projean, Denis; Dautrey, Sophie; Vu, Huy Khan; Groblewski, Thierry; Brazier, J. L.; Ducharme, Julie

doi:10.1007/s11095-004-9010-6

Cited by 29 publications

(36 citation statements)

References 34 publications

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“…Our results clearly demonstrate that arthritis induced by FCA does not alter the pharmacokinetic behaviors of diclofenac in rats. However, some reports have shown that acute inflammation may alter the pharmacokinetics of NSAIDs [24,25] . This discrepancy may come from the oscillations of activities of CYP enzymes over period of inflammation and drugs [25] .…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic-pharmacodynamic modeling of diclofenac in normal and Freund's complete adjuvant-induced arthritic rats

Zhang

Guo

et al. 2012

Acta Pharmacol Sin

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Aim: To characterize pharmacokinetic-pharmacodynamic modeling of diclofenac in Freund's complete adjuvant (FCA)-induced arthritic rats using prostaglandin E 2 (PGE 2 ) as a biomarker. Methods: The pharmacokinetics of diclofenac was investigated using 20-day-old arthritic rats. PGE 2 level in the rats was measured using an enzyme immunoassay. A pharmacokinetic-pharmacodynamic (PK-PD) model was developed to illustrate the relationship between the plasma concentration of diclofenac and the inhibition of PGE 2 production. The inhibition of diclofenac on lipopolysaccharide (LPS)-induced PGE 2 production in blood cells was investigated in vitro. Results: Similar pharmacokinetic behavior of diclofenac was found both in normal and FCA-induced arthritic rats. Diclofenac significantly decreased the plasma levels of PGE 2 in both normal and arthritic rats. The inhibitory effect on PGE 2 levels in the plasma was in proportion to the plasma concentration of diclofenac. No delay in the onset of inhibition was observed, suggesting that the effect compartment was located in the central compartment. An inhibitory effect sigmoid I max model was selected to characterize the relationship between the plasma concentration of diclofenac and the inhibition of PGE 2 production in vivo. The I max model was also used to illustrate the inhibition of diclofenac on LPS-induced PGE 2 production in blood cells in vitro. Conclusion: Arthritis induced by FCA does not alter the pharmacokinetic behaviors of diclofenac in rats, but the pharmacodynamics of diclofenac is slightly affected. A PK-PD model characterizing an inhibitory effect sigmoid I max can be used to fit the relationship between the plasma PGE 2 and diclofenac levels in both normal rats and FCA-induced arthritic rats.

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetic-pharmacodynamic modeling of diclofenac in normal and Freund's complete adjuvant-induced arthritic rats

Zhang

Guo

et al. 2012

Acta Pharmacol Sin

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“…1, B and C). A confounding factor with the use of CFA is that it induces inflammation, which decreases the expression of P450s, and therefore it can inhibit drug bioactivation (Monshouwer et al, 1996;Projean et al, 2005). In the initial experiments, we treated animals with INH during the immunization schedule; later, we waited for 4 weeks from the last immunization with hepatic protein in IFA before starting INH (Fig.…”

Section: Resultsmentioning

confidence: 99%

Paradoxical Attenuation of Autoimmune Hepatitis by Oral Isoniazid in Wild-Type andN-Acetyltransferase–Deficient Mice

et al. 2014

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Isoniazid (INH) treatment can cause serious liver injury and autoimmunity. There are now several lines of evidence that INHinduced liver injury is immune mediated, but this type of liver injury has not been reproduced in animals, possibly because immune tolerance is the dominant response of the liver. In this study, we immunized mice with isonicotinic acid (INA)-modified proteins and Freund's adjuvant, which led to mild experimental autoimmune hepatitis (EAH) with an increase in cells staining positive for F4/80, CD11b, CD8, CD4, CD45R, and KI67. We expected that subsequent treatment of mice with oral INH would lead to more serious immune-mediated liver injury, but paradoxically it markedly attenuated the EAH caused by immunization with INA-modified hepatic proteins. In addition, patients of the slow acetylator phenotype are at increased risk of INH-induced liver injury. Treatment of arylamine N-acetyltransferase-deficient Nat1/2(2/2) mice with INH for up to 5 weeks produced mild increases in glutamate and sorbitol dehydrogenase activities, but not severe liver injury. Female Nat1/2(2/2) mice treated with INH for 1, 3, or 7 days developed steatosis, an increase in Oil Red O staining, and abnormal mitochondrial morphology in the liver. A decrease in M1 and an increase in M2a and M2b macrophages was observed in female Nat1/2(2/2) mice treated with INH for 1, 3, or 7 days; these changes returned to baseline levels by day 35. These data indicate that INH has immunosuppressive effects, even though it is also known to induce autoantibody production and a lupuslike autoimmune syndrome in humans.

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“…In rat lipopolysaccharide-or Freund's complete adjuvant-induced inflammation, mRNA levels of CYP3A2 were reduced by 60% of the control, and those of CYP3A1 were reduced by approximately 85% of the control (Sewer and Morgan, 1998;Projean et al, 2005). It seems that down-regulation of hepatic CYP3A genes is a common feature of inflammatory states, and it can also be applied to our PAN-induced nephrosis model.…”

Section: Increased Absorption Of Cyclosporine a In A Nephrosis Modelmentioning

confidence: 90%

Contribution of Down-Regulation of Intestinal and Hepatic Cytochrome P450 3A to Increased Absorption of Cyclosporine A in a Rat Nephrosis Model

Fujita¹,

Yasuda²,

Kamata³

et al. 2008

J Pharmacol Exp Ther

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This study examined the contribution of changes in regulation of intestinal and hepatic cytochrome P450 3A (CYP3A) and multidrug resistance transporter 1 (Mdr1) to absorption of cyclosporine A (CsA) in a rat nephrosis model. Interleukin (IL)-6 was also measured. Puromycin aminonucleoside at a dose of 20 mg/100 g was administered intravenously. Tissue samples were dissected out from the upper and middle intestines and liver after development of nephrosis to measure the expression levels of mRNA and protein. CsA at a dose of 0.5 mg/100 g was administered into a closed loop of the upper and middle intestines. Blood from the inferior vena cava (IVC) and portal vein was taken until 30 min after administration. The expression levels of CYP3A decreased markedly, whereas those of Mdr1 showed large interindividual variations for all of the tissues in the nephrotic rats. Plasma concentrations of CsA reached higher levels in the nephrotic than in the control rats and were higher when administered from the upper than the middle intestine in both the portal vein and IVC. IL-6 increased in urine in the nephrotic rats. In summary, intestinal and hepatic CYP3A were down-regulated in the nephrosis model accompanying the increased levels of IL-6. Consistent results were not obtained for the regulation of Mdr1. In conclusion, these findings suggest that the down-regulation of CYP3A in the upper intestine and liver predominantly contributes to the increase in CsA absorption, and Mdr1 showed less contribution in this rat nephrosis model.

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Selective Downregulation of Hepatic Cytochrome P450 Expression and Activity in a Rat Model of Inflammatory Pain

Abstract: These early biochemical and metabolic modifications may have pharmacokinetic and pharmacodynamic consequences when hepatically cleared drugs are administered to FCA-treated rats, especially within the first 24-72 h post-FCA.

Cited by 29 publications

References 34 publications

Pharmacokinetic-pharmacodynamic modeling of diclofenac in normal and Freund's complete adjuvant-induced arthritic rats

Pharmacokinetic-pharmacodynamic modeling of diclofenac in normal and Freund's complete adjuvant-induced arthritic rats

Paradoxical Attenuation of Autoimmune Hepatitis by Oral Isoniazid in Wild-Type andN-Acetyltransferase–Deficient Mice

Contribution of Down-Regulation of Intestinal and Hepatic Cytochrome P450 3A to Increased Absorption of Cyclosporine A in a Rat Nephrosis Model

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