Pharmacokinetics and pharmacodynamics of paclitaxel with carboplatin or gemcitabine, and effects of CYP3A5 and MDR1 polymorphisms in patients with urogenital cancers

Mari Jiko, Ikuko Yano, Eriko Sato, Kazushige Takahashi, Hideyuki Motohashi, Satohiro Masuda, Masahiro Okuda, Noriyuki Ito, Eijiro Nakamura, Takehiko Segawa, Toshiyuki Kamoto, Osamu Ogawa, Ken Ichi Inui

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Abstract

Background. We investigated the pharmacokinetics and pharmacodynamics of paclitaxel with carboplatin or gemcitabine in patients with urogenital cancer to clarify the significance of monitoring of the serum concentration of paclitaxel. Methods. Paclitaxel was administered at 175 mg/m2 or 150 mg/m2 to patients with hormone-refractory prostate cancer (n = 10) or advanced transitional cell carcinoma (n = 6) along with carboplatin or gemcitabine, respectively. The relationships between pharmacokinetic parameters and hematological adverse effects, as well as pharmacological effects, were examined. The effects of patient characteristics, including single-nucleotide polymorphisms of MDR1(ABCB1), CYP2C8, CYP3A4, and CYP3A5, on the total body clearance of paclitaxel were evaluated. Results. Total body clearance and volume of distribution at a steady-state after the intravenous infusion of paclitaxel were not significantly different between patients with carboplatin or gemcitabine. The percent decreases in neutrophils and platelets for the regimen with gemcitabine were significantly greater than those with carboplatin, and showed a significant positive relationship with the observed concentration at the end of infusion or time above 0.1-μM concentration of paclitaxel. Post-therapy decreases in prostate-specific antigen were not positively correlated with the extent of paclitaxel exposure in the prostate cancer patients. Neither the polymorphisms at exon 26 (C3435T) and at exon 21 (G2677A/T) in MDR1 nor the CYP3A5*1 allele significantly affected the total body clearance of paclitaxel. Conclusion. The hematological side effects of paclitaxel were intensified by gemcitabine, and were correlated with paclitaxel pharmacokinetics. Monitoring of the serum concentration of paclitaxel will facilitate the therapy, with less myelosuppression and without any loss of therapeutic efficacy.

Original languageEnglish
Pages (from-to)284-290
Number of pages7
JournalInternational Journal of Clinical Oncology
Volume12
Issue number4
DOIs
Publication statusPublished - Aug 1 2007

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gemcitabine
Urogenital Neoplasms
Cytochrome P-450 CYP3A
Carboplatin
Paclitaxel
Pharmacokinetics
Exons
Prostatic Neoplasms
Transitional Cell Carcinoma

All Science Journal Classification (ASJC) codes

  • Surgery
  • Hematology
  • Oncology

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Pharmacokinetics and pharmacodynamics of paclitaxel with carboplatin or gemcitabine, and effects of CYP3A5 and MDR1 polymorphisms in patients with urogenital cancers. / Jiko, Mari; Yano, Ikuko; Sato, Eriko; Takahashi, Kazushige; Motohashi, Hideyuki; Masuda, Satohiro; Okuda, Masahiro; Ito, Noriyuki; Nakamura, Eijiro; Segawa, Takehiko; Kamoto, Toshiyuki; Ogawa, Osamu; Inui, Ken Ichi.

In: International Journal of Clinical Oncology, Vol. 12, No. 4, 01.08.2007, p. 284-290.

Research output: Contribution to journalArticle

Jiko, Mari ; Yano, Ikuko ; Sato, Eriko ; Takahashi, Kazushige ; Motohashi, Hideyuki ; Masuda, Satohiro ; Okuda, Masahiro ; Ito, Noriyuki ; Nakamura, Eijiro ; Segawa, Takehiko ; Kamoto, Toshiyuki ; Ogawa, Osamu ; Inui, Ken Ichi. / Pharmacokinetics and pharmacodynamics of paclitaxel with carboplatin or gemcitabine, and effects of CYP3A5 and MDR1 polymorphisms in patients with urogenital cancers. In: International Journal of Clinical Oncology. 2007 ; Vol. 12, No. 4. pp. 284-290.
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abstract = "Background. We investigated the pharmacokinetics and pharmacodynamics of paclitaxel with carboplatin or gemcitabine in patients with urogenital cancer to clarify the significance of monitoring of the serum concentration of paclitaxel. Methods. Paclitaxel was administered at 175 mg/m2 or 150 mg/m2 to patients with hormone-refractory prostate cancer (n = 10) or advanced transitional cell carcinoma (n = 6) along with carboplatin or gemcitabine, respectively. The relationships between pharmacokinetic parameters and hematological adverse effects, as well as pharmacological effects, were examined. The effects of patient characteristics, including single-nucleotide polymorphisms of MDR1(ABCB1), CYP2C8, CYP3A4, and CYP3A5, on the total body clearance of paclitaxel were evaluated. Results. Total body clearance and volume of distribution at a steady-state after the intravenous infusion of paclitaxel were not significantly different between patients with carboplatin or gemcitabine. The percent decreases in neutrophils and platelets for the regimen with gemcitabine were significantly greater than those with carboplatin, and showed a significant positive relationship with the observed concentration at the end of infusion or time above 0.1-μM concentration of paclitaxel. Post-therapy decreases in prostate-specific antigen were not positively correlated with the extent of paclitaxel exposure in the prostate cancer patients. Neither the polymorphisms at exon 26 (C3435T) and at exon 21 (G2677A/T) in MDR1 nor the CYP3A5*1 allele significantly affected the total body clearance of paclitaxel. Conclusion. The hematological side effects of paclitaxel were intensified by gemcitabine, and were correlated with paclitaxel pharmacokinetics. Monitoring of the serum concentration of paclitaxel will facilitate the therapy, with less myelosuppression and without any loss of therapeutic efficacy.",
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T1 - Pharmacokinetics and pharmacodynamics of paclitaxel with carboplatin or gemcitabine, and effects of CYP3A5 and MDR1 polymorphisms in patients with urogenital cancers

AU - Jiko, Mari

AU - Yano, Ikuko

AU - Sato, Eriko

AU - Takahashi, Kazushige

AU - Motohashi, Hideyuki

AU - Masuda, Satohiro

AU - Okuda, Masahiro

AU - Ito, Noriyuki

AU - Nakamura, Eijiro

AU - Segawa, Takehiko

AU - Kamoto, Toshiyuki

AU - Ogawa, Osamu

AU - Inui, Ken Ichi

PY - 2007/8/1

Y1 - 2007/8/1

N2 - Background. We investigated the pharmacokinetics and pharmacodynamics of paclitaxel with carboplatin or gemcitabine in patients with urogenital cancer to clarify the significance of monitoring of the serum concentration of paclitaxel. Methods. Paclitaxel was administered at 175 mg/m2 or 150 mg/m2 to patients with hormone-refractory prostate cancer (n = 10) or advanced transitional cell carcinoma (n = 6) along with carboplatin or gemcitabine, respectively. The relationships between pharmacokinetic parameters and hematological adverse effects, as well as pharmacological effects, were examined. The effects of patient characteristics, including single-nucleotide polymorphisms of MDR1(ABCB1), CYP2C8, CYP3A4, and CYP3A5, on the total body clearance of paclitaxel were evaluated. Results. Total body clearance and volume of distribution at a steady-state after the intravenous infusion of paclitaxel were not significantly different between patients with carboplatin or gemcitabine. The percent decreases in neutrophils and platelets for the regimen with gemcitabine were significantly greater than those with carboplatin, and showed a significant positive relationship with the observed concentration at the end of infusion or time above 0.1-μM concentration of paclitaxel. Post-therapy decreases in prostate-specific antigen were not positively correlated with the extent of paclitaxel exposure in the prostate cancer patients. Neither the polymorphisms at exon 26 (C3435T) and at exon 21 (G2677A/T) in MDR1 nor the CYP3A5*1 allele significantly affected the total body clearance of paclitaxel. Conclusion. The hematological side effects of paclitaxel were intensified by gemcitabine, and were correlated with paclitaxel pharmacokinetics. Monitoring of the serum concentration of paclitaxel will facilitate the therapy, with less myelosuppression and without any loss of therapeutic efficacy.

AB - Background. We investigated the pharmacokinetics and pharmacodynamics of paclitaxel with carboplatin or gemcitabine in patients with urogenital cancer to clarify the significance of monitoring of the serum concentration of paclitaxel. Methods. Paclitaxel was administered at 175 mg/m2 or 150 mg/m2 to patients with hormone-refractory prostate cancer (n = 10) or advanced transitional cell carcinoma (n = 6) along with carboplatin or gemcitabine, respectively. The relationships between pharmacokinetic parameters and hematological adverse effects, as well as pharmacological effects, were examined. The effects of patient characteristics, including single-nucleotide polymorphisms of MDR1(ABCB1), CYP2C8, CYP3A4, and CYP3A5, on the total body clearance of paclitaxel were evaluated. Results. Total body clearance and volume of distribution at a steady-state after the intravenous infusion of paclitaxel were not significantly different between patients with carboplatin or gemcitabine. The percent decreases in neutrophils and platelets for the regimen with gemcitabine were significantly greater than those with carboplatin, and showed a significant positive relationship with the observed concentration at the end of infusion or time above 0.1-μM concentration of paclitaxel. Post-therapy decreases in prostate-specific antigen were not positively correlated with the extent of paclitaxel exposure in the prostate cancer patients. Neither the polymorphisms at exon 26 (C3435T) and at exon 21 (G2677A/T) in MDR1 nor the CYP3A5*1 allele significantly affected the total body clearance of paclitaxel. Conclusion. The hematological side effects of paclitaxel were intensified by gemcitabine, and were correlated with paclitaxel pharmacokinetics. Monitoring of the serum concentration of paclitaxel will facilitate the therapy, with less myelosuppression and without any loss of therapeutic efficacy.

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