Comparative pharmacokinetics of escalating doses of doxorubicin in patients with metastatic breast cancer.

2.50
Hdl Handle:
http://hdl.handle.net/10541/109856
Title:
Comparative pharmacokinetics of escalating doses of doxorubicin in patients with metastatic breast cancer.
Authors:
Bronchud, Miguel H; Margison, Jennifer M; Howell, Anthony ( 0000-0002-6233-719X ) ; Lind, Michael J; Lucas, S B; Wilkinson, Peter M
Abstract:
Recombinant human granulocyte colony-stimulating factor (G-CSF) has been shown to reduce neutropenia following cytotoxic therapy, thereby enabling dose escalation to improve the response rate. It is important to know whether drug kinetics change as doses are increased. Doxorubicin was selected because of its broad spectrum of activity and its known efficacy in metastatic breast cancer. Doses of 75, 100, 125 and 150 mg/m2 were given to 11 patients with metastatic breast cancer by infusion over 30 min. Serum concentrations of parent drug and metabolites were determined during the first 48 h following the infusion by high-performance liquid chromatography (HPLC). The serum concentration vs time curve decayed as a triple exponential function in four patients and as a double exponential function in seven. A four-compartment model, one central and three peripheral, would predict concentrations to within 1 SE of the observed values. Doxorubicinol was the principal metabolite, and doxorubicinone and 7-deoxydoxorubicinone were clearly identified. There was a linear increase in the AUC infinity with dose. In addition, a small and transient increase in circulating levels of doxorubicinol and other important metabolites was observed 6 h following the administration of doxorubicin, which suggests the existence of an enterohepatic, or other, re-circulation mechanism. We conclude that in the dose range selected the kinetics of doxorubicin are linear and that the increase in toxicities seen with the higher doses of doxorubicin, following the second and third fortnightly administration, may be due to intracellular drug accumulation in tissues.
Affiliation:
Department of Medical Oncology, Christie Hospital and Holt Radium Institute, Manchester, England.
Citation:
Comparative pharmacokinetics of escalating doses of doxorubicin in patients with metastatic breast cancer. 1990, 25 (6):435-9 Cancer Chemother. Pharmacol.
Journal:
Cancer Chemotherapy and Pharmacology
Issue Date:
1990
URI:
http://hdl.handle.net/10541/109856
DOI:
10.1007/BF00686055
PubMed ID:
2311172
Type:
Article
Language:
en
ISSN:
0344-5704
Appears in Collections:
All Christie Publications ; All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorBronchud, Miguel Hen
dc.contributor.authorMargison, Jennifer Men
dc.contributor.authorHowell, Anthonyen
dc.contributor.authorLind, Michael Jen
dc.contributor.authorLucas, S Ben
dc.contributor.authorWilkinson, Peter Men
dc.date.accessioned2010-08-18T15:02:06Z-
dc.date.available2010-08-18T15:02:06Z-
dc.date.issued1990-
dc.identifier.citationComparative pharmacokinetics of escalating doses of doxorubicin in patients with metastatic breast cancer. 1990, 25 (6):435-9 Cancer Chemother. Pharmacol.en
dc.identifier.issn0344-5704-
dc.identifier.pmid2311172-
dc.identifier.doi10.1007/BF00686055-
dc.identifier.urihttp://hdl.handle.net/10541/109856-
dc.description.abstractRecombinant human granulocyte colony-stimulating factor (G-CSF) has been shown to reduce neutropenia following cytotoxic therapy, thereby enabling dose escalation to improve the response rate. It is important to know whether drug kinetics change as doses are increased. Doxorubicin was selected because of its broad spectrum of activity and its known efficacy in metastatic breast cancer. Doses of 75, 100, 125 and 150 mg/m2 were given to 11 patients with metastatic breast cancer by infusion over 30 min. Serum concentrations of parent drug and metabolites were determined during the first 48 h following the infusion by high-performance liquid chromatography (HPLC). The serum concentration vs time curve decayed as a triple exponential function in four patients and as a double exponential function in seven. A four-compartment model, one central and three peripheral, would predict concentrations to within 1 SE of the observed values. Doxorubicinol was the principal metabolite, and doxorubicinone and 7-deoxydoxorubicinone were clearly identified. There was a linear increase in the AUC infinity with dose. In addition, a small and transient increase in circulating levels of doxorubicinol and other important metabolites was observed 6 h following the administration of doxorubicin, which suggests the existence of an enterohepatic, or other, re-circulation mechanism. We conclude that in the dose range selected the kinetics of doxorubicin are linear and that the increase in toxicities seen with the higher doses of doxorubicin, following the second and third fortnightly administration, may be due to intracellular drug accumulation in tissues.en
dc.language.isoenen
dc.subjectBreast Canceren
dc.subject.meshAdult-
dc.subject.meshBreast Neoplasms-
dc.subject.meshChromatography, High Pressure Liquid-
dc.subject.meshDose-Response Relationship, Drug-
dc.subject.meshDoxorubicin-
dc.subject.meshFemale-
dc.subject.meshHalf-Life-
dc.subject.meshHumans-
dc.subject.meshMetabolic Clearance Rate-
dc.subject.meshMiddle Aged-
dc.subject.meshNaphthacenes-
dc.titleComparative pharmacokinetics of escalating doses of doxorubicin in patients with metastatic breast cancer.en
dc.typeArticleen
dc.contributor.departmentDepartment of Medical Oncology, Christie Hospital and Holt Radium Institute, Manchester, England.en
dc.identifier.journalCancer Chemotherapy and Pharmacologyen

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