Impact of Endotoxin-Induced Changes in P-Glycoprotein Expression on Disposition of Doxorubicin in Mice

Hartmann, Georgy; Vassileva, Vessela; Piquette-Miller, Micheline

doi:10.1124/dmd.104.002568

Cited by 72 publications

(56 citation statements)

References 26 publications

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“…Moreover, the P-gp and CYP3A levels in the liver and intestine were not coordinately regulated, which is consistent with the findings of Lown et al (1994), who showed that the hepatic CYP3A4 activity in humans did not correlate with the intestinal CYP3A4 activity and protein content. Such tissue-specific response of P-gp and/or CYP3A expression to treatment has been reported by other researchers (Hartmann et al, 2005) and is thought to facilitate the removal of potentially toxic substances in abnormal states where the excretory capacity of a specific organ is diminished. There is evidence that curcumin may modulate the transcription of CYP3A through the pregnane X receptor (PXR) (Liu et al, 2006).…”

Section: Discussionmentioning

confidence: 84%

Impact of Curcumin-Induced Changes in P-Glycoprotein and CYP3A Expression on the Pharmacokinetics of Peroral Celiprolol and Midazolam in Rats

Zhang

Tan²,

Lim³

2006

Drug Metab Dispos

125

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ABSTRACT:The aim of this study was to evaluate whether curcumin could modulate P-glycoprotein (P-gp) and CYP3A expression, and in turn modify the pharmacokinetic profiles of P-gp and CYP3A substrates in male Sprague-Dawley rats. Intragastric gavage of the rats with 60 mg/kg curcumin for 4 consecutive days led to a down-regulation of the intestinal P-gp level. There was a concomitant upregulation of hepatic P-gp level, but the renal P-gp level was unaffected. Curcumin also attenuated the CYP3A level in the small intestine but induced CYP3A expression in the liver and kidney. Regular curcumin consumption also caused the C max and area under the concentration-time curve (AUC 0-8 and total AUC) of peroral celiprolol (a P-gp substrate with negligible cytochrome P450 metabolism) at 30 mg/kg to increase, but the apparent oral clearance (CL oral ) of the drug was reduced. Similarly, rats treated with curcumin for 4 consecutive days showed higher AUC (AUC 0-4 and total AUC) and lower CL oral for peroral midazolam (a CYP3A substrate that does not interact with the P-gp) at 20 mg/kg in comparison with vehicle-treated rats. In contrast, curcumin administered 30 min before the respective drug treatments did not significantly modify the pharmacokinetic parameters of the drugs. Analysis of the data suggests that the changes in the pharmacokinetic profiles of peroral celiprolol and midazolam in the rat model were contributed mainly by the curcumin-mediated down-regulation of intestinal P-gp and CYP3A protein levels, respectively.

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Section: Discussionmentioning

confidence: 84%

Impact of Curcumin-Induced Changes in P-Glycoprotein and CYP3A Expression on the Pharmacokinetics of Peroral Celiprolol and Midazolam in Rats

Zhang

Tan²,

Lim³

2006

Drug Metab Dispos

125

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“…Nevertheless in both species, a decreased PGP protein expression is seen (Tang et al, 2000;Hartmann et al, 2001;Goralski et al, 2003). Subsequent pharmacokinetic studies confirmed the fact that inflammation-mediated decreases in the hepatic expression of Mdr1a/PGP in endotoxin-treated mice and rats were associated with corresponding changes in function and significant reductions in the hepatic accumulation and biliary clearance of model substrates including doxorubicin and 99m Tc-sestamibi (Hartmann et al, 2005;Wang et al, 2005).…”

Section: Regulation Of Drug Transporters In Inflammation (Mp-m)mentioning

confidence: 85%

“…Endotoxin-induced down-regulation of PGP/ Mdr1a in brain tissues has also been found to increase intracranial drug accumulation in rodents. Increased accumulation of doxorubicin, which corresponded to decreased PGP protein expression, was observed in the brains of endotoxin-treated mice (Hartmann et al, 2005). Likewise, systemic and CNS inflammation produced by i.p.…”

Section: Regulation Of Drug Transporters In Inflammation (Mp-m)mentioning

confidence: 89%

“…The resulting functional defects in multidrug resistance protein (Mdr) 1a activity in acute inflammation are manifest by reduced hepatic transport of doxorubicin and 99m Tc-labeled sestamibi (Hartmann et al, 2005;Wang et al, 2005). We therefore examined the expression of a number of transport protein genes in the livers of EHS tumor-bearing mice.…”

Section: Transcriptional Repression Of Hepaticmentioning

confidence: 99%

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Regulation of Drug-Metabolizing Enzymes and Transporters in Infection, Inflammation, and Cancer

et al. 2008

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ABSTRACT:This article is a report on a symposium sponsored by the American Society for Pharmacology and Experimental Therapeutics and held at the Experimental Biology 07 meeting in Washington, DC. The presentations discussed the phenomenology, clinical consequences, and underlying mechanisms of cytochrome P450 and drug transporter regulation by inflammatory and infectious stimuli. Although considerable insights into the links between inflammatory mediators and altered hepatic drug clearance pathways have been gained from previous studies with acute inflammatory stimuli, this symposium highlighted recent advances in understanding how these processes operate in other organs and chronic inflammatory states relevant to human diseases. The development of mouse models of live bacterial infection provides excellent opportunities to explore the impact of infection on drug metabolism beyond the well characterized effects of bacterial endotoxin. Altered levels of cytochromes P450 and especially drug transporters due to inflammation in brain, intestine, and placenta have significant implications for the use of many drugs in diverse clinical settings. The consequences of inflammatory cytokine production by tumors for drug safety and efficacy in cancer patients were outlined. Repression of drug clearance pathways by tumor-derived cytokines may result in extreme toxicity to chemotherapy, compromising treatment of many cancers. It is fitting that, in honoring the career contributions and achievements of Dr. Kenneth W. Renton, this symposium reinforced the clinical relevance of this field.Inflammation regulates the expression, activity, and functions of many drug-metabolizing enzymes and drug transporters. Although impairment of drug-metabolizing enzyme activities during inflammation has been known to occur for half a century, regulation of transporters by inflammation was recognized relatively recently, in the last decade. Although the regulation of both cytochrome P450s (P450s) and drug transporters has profound implications for clinical drug therapy in disease states, research on inflammation in drug metabolism and transporters has tended to proceed in parallel. This symposium was organized to bring the areas together to identify commonalities and differences in the regulation of transporters and drug-metabolizing enzymes and to promote cross-fertilization of knowledge. It is appropriate then, that this symposium also recognized the career and contributions of Dr. Kenneth W. Renton on the occasion of his retirement.The diverse presentations on regulation of both P450 enzymes and drug transporters revealed that the regulation of both systems in inflammation, infection, and cancer have much in common. In the face of a global inflammatory stimulus such as bacterial endotoxin

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“…Others have also reported infection or inflammation-mediated increases in the mRNA and protein expression of MDR1 in kidney (Hartmann et al, 2005;Heemskerk et al, 2010). Increased renal expression of MDR1 in endotoxin-treated mice was associated with increased renal elimination of the MDR1 substrate doxorubicin (Hartmann et al, 2005). It is plausible that malaria-imposed changes could impact renal clearance of antimalarials and other substrates.…”

Section: Discussionmentioning

confidence: 99%

Malaria Infection Alters the Expression of Hepatobiliary and Placental Drug Transporters in Pregnant Mice

et al. 2013

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Preventing and treating malaria in pregnancy is a global health priority. However little is known regarding the impact of malaria infection on the maternal and fetal disposition of pharmaceuticals and other xenobiotics. Our objective was to characterize expression of key determinants of drug-disposition in maternal and fetal tissues in a validated murine model of experimental placental malaria. Balb/c mice were infected with Plasmodium berghei at mid gestation [gestational day (GD) 13] and maternal, placental, and fetal tissues were collected at GD19. Expression of key ABC drug transporters and Cyp3a11 was examined by quantitative polymerase chain reaction. Western blotting was used to examine the protein expression of multidrug resistance protein 1 (MDR1, ABCB1). Compared with controls, placental mRNA expression of Abcb1a, Abcb1b, Abcc1, Abcc2, Abcc3, and Abcg2 were significantly downregulated in the malaria-infected group (P < 0.05), as was placental MDR1 protein (P < 0.05). Significantly decreased hepatic expression of Abcc2, Abcg2, and Abcb11 and significantly increased expression of Abcb1b, Abcc1, and Abcc3 were seen in malaria-infected dams (P < 0.05) in comparison with uninfected controls. The expression of Abcb1a and Abcg2 was significantly decreased in fetal liver of infected dams, whereas levels of Abcb1b were increased (P < 0.05). Maternal and fetal hepatic expression of Cyp3a11 was significantly downregulated in the malaria group (P < 0.05). Together, malaria-induced alterations in the expression of transporters and drug-metabolizing enzymes in maternal and fetal tissues may alter the disposition of endogenous and therapeutic substrates, potentially impacting maternal and fetal outcomes.

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Impact of Endotoxin-Induced Changes in P-Glycoprotein Expression on Disposition of Doxorubicin in Mice

Cited by 72 publications

References 26 publications

Impact of Curcumin-Induced Changes in P-Glycoprotein and CYP3A Expression on the Pharmacokinetics of Peroral Celiprolol and Midazolam in Rats

Impact of Curcumin-Induced Changes in P-Glycoprotein and CYP3A Expression on the Pharmacokinetics of Peroral Celiprolol and Midazolam in Rats

Regulation of Drug-Metabolizing Enzymes and Transporters in Infection, Inflammation, and Cancer

Malaria Infection Alters the Expression of Hepatobiliary and Placental Drug Transporters in Pregnant Mice

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