Factors Affecting Cytochrome P-450 3A Activity in Cancer Patients

Baker, Sharyn D.; Schaik, Ron H.N. van; Rivory, Laurent P.; Tije, Albert J. ten; Dinh, Kha; Graveland, Wilfried J.; Schenk, Paul W.; Charles, Kellie A.; Clarke, Stephen; Carducci, Michael A.; McGuire, William P.; Dawkins, Fitzroy W.; Gelderblom, Hans; Verweij, Jaap; Sparreboom, Alex

doi:10.1158/1078-0432.ccr-04-1371

Cited by 119 publications

(88 citation statements)

References 63 publications

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“…24 While increased AAG may decrease the unbound fraction of imatinib, potentially altering both drug exposure and clearance, higher AAG has also been correlated with decreased CYP3A4 activity. 25 Indeed, Delbaldo et al reported a correlation between increased AAG levels and decreased imatinib clearance. 26 In order to conclusively assess the possibility of pharmacokinetic resistance arising from modulation of drug disposition via changes in protein binding, metabolism, or transport, long-term pharmacokinetic studies must be embarked upon.…”

Section: Discussionmentioning

confidence: 99%

Lack of ABC transporter autoinduction in mice following long-term exposure to imatinib

Gardner

Sparreboom²,

Verweij³

et al. 2008

Cancer Biology & Therapy

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This manuscript has been published online, prior to printing.Once the issue is complete and page numbers have been assigned, the citation will change accordingly.Purpose: Chronic imatinib exposure has been shown to result in upregulation of the ABCB1 (P-glycoprotein) and ABCG2 (BCRP) transporters in vitro, for which imatinib is a substrate. This finding, along a trend towards increasing imatinib clearance over time in patients, has resulted in the suggestion that pharmacokinetic resistance may be contributing to eventual treatment failure. Here, we sought to determine the effects of long-term imatinib exposure on apparent oral clearance and transporter expression in vivo.Results: Plasma and liver concentrations of imatinib did not change significantly (p > 0.1) over the course of treatment, suggesting that steady-state had been reached. There was no increase in Abcb1 or Abcg2 expression in liver samples, whereas expression of these transporters in intestinal samples was highly variable, and no increase was apparent.Methods: Male BALB/c mice were treated daily-times 5 with oral imatinib at a dose of 50 mg/kg for 4 consecutive weeks. Imatinib concentrations were measured in plasma and liver tissue prior to treatment and following each week of dosing. Western blotting of liver and intestinal tissue lysates was performed to assess expression of Abcb1 and Abcg2.Conclusions: Imatinib does not appear to cause upregulation of ABC transporters in the hepatic and intestinal compartments in mice. These data do not support the possibility that autoinduction contributes to the development of resistance to imatinib.

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Section: Discussionmentioning

confidence: 99%

Lack of ABC transporter autoinduction in mice following long-term exposure to imatinib

Gardner

Sparreboom²,

Verweij³

et al. 2008

Cancer Biology & Therapy

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“…One potential source of interindividual variability in CYP3A-mediated drug metabolism is the genetic diversity in human CYP3A genes. However, recent studies in cancer patients have found that single nucleotide polymorphisms in the CYP3A4 gene are unlikely to make a significant contribution to differences in CYP3A activity relevant to chemotherapy, as assessed by erythromycin breath test, midazolam clearance, or paclitaxel pharmacokinetics (Baker et al, 2004;Henningsson et al, 2005;Lepper et al, 2005). Therefore, it is important to elucidate the impact of one other source of variability in hepatic drug metabolism, namely cancer-induced inflammation, as it is present in at least 60% of patients with advanced cancer.…”

Section: Transcriptional Repression Of Hepaticmentioning

confidence: 99%

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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“…17 Breath samples were shipped to Metabolic Solutions (Nashua, NH) for measurement of breath carbon dioxide. The data were reported as the flux of 14 CO 2.…”

Section: Erythromycin Breath Test (Ermbt)mentioning

confidence: 99%

Population Pharmacokinetic Model for Docetaxel in Patients with Varying Degrees of Liver Function: Incorporating Cytochrome P450 3A Activity Measurements

Hooker

Tije

Carducci

et al. 2008

Clin Pharmacol Ther

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The relationship between cytochrome P4503A4 (CYP3A4) activity and docetaxel clearance in patients with varying degrees of liver function (LF) was evaluated. Docetaxel 40, 50, or 75 mg/m 2 was administered to 85 patients with advanced cancer; 23 of 77 evaluable patients had abnormalities in liver function tests. Baseline CYP3A activity was assessed using the erythromycin breath test (ERMBT). Pharmacokinetic studies and toxicity assessments were performed during cycle 1 of therapy and population modeling was performed using NONMEM. Docetaxel unbound clearance was lower (317 vs. 470 L/h) and more variable in patients with liver function abnormalities compared to patients with normal LF. Covariates evaluated accounted for 83% of variability on clearance in patients with liver dysfunction, with CYP3A4 activity accounting for 47% of variation; covariates accounted for only 23% of variability in patients with normal LF. The clinical utility of the ERMBT may be in identifying safe docetaxel doses for patients with LF abnormalities.

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Factors Affecting Cytochrome P-450 3A Activity in Cancer Patients

Cited by 119 publications

References 63 publications

Lack of ABC transporter autoinduction in mice following long-term exposure to imatinib

Lack of ABC transporter autoinduction in mice following long-term exposure to imatinib

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

Population Pharmacokinetic Model for Docetaxel in Patients with Varying Degrees of Liver Function: Incorporating Cytochrome P450 3A Activity Measurements

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