title: Pharmacokinetics and pharmacodynamics of paclitaxel with carboplatin or gemcitabine, and effects of CYP3A5 and MDR1 polymorphisms in patients with urogenital cancers.
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/m(2) or 150 mg/m(2) 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-microM 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.
  
  
  CONCLUSIONS
  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.
authors: Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto, 606-8507, Japan.
authors: Mari
authors: M
authors: Jiko
authors: Ikuko
authors: I
authors: Yano
authors: Eriko
authors: E
authors: Sato
authors: Kazushige
authors: K
authors: Takahashi
authors: Hideyuki
authors: H
authors: Motohashi
authors: Satohiro
authors: S
authors: Masuda
authors: Masahiro
authors: M
authors: Okuda
authors: Noriyuki
authors: N
authors: Ito
authors: Eijiro
authors: E
authors: Nakamura
authors: Takehiko
authors: T
authors: Segawa
authors: Toshiyuki
authors: T
authors: Kamoto
authors: Osamu
authors: O
authors: Ogawa
authors: Ken-Ichi
authors: K
authors: Inui
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D016190:Carboplatin / Q000008:administration & dosage; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005838:Genotype; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D011110:Polymorphism, Genetic; D017430:Prostate-Specific Antigen / Q000097:blood; D014565:Urogenital Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000093542:Gemcitabine
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003841:Deoxycytidine; D003577:Cytochrome P-450 Enzyme System; D016190:Carboplatin; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D017430:Prostate-Specific Antigen; D017239:Paclitaxel; D000093542:Gemcitabine
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