The influence of granisetron on the pharmacokinetics and pharmacodynamics of docetaxel in Asian lung cancer patients.
BACKGROUND
Docetaxel, which undergoes hepatic metabolism via cytochrome P450 3A4, is a promising anticancer agent. Toxicity is serious problem, however, because it is difficult to predict the cytochrome P450 3A4 activity of the drug. Moreover, drug-drug interactions involving cytochrome P450 3A4 enzymes are important. Granisetron, a selective antagonist of the 5-hydroxytryptamine3 receptor, also undergoes hepatic metabolism via cytochrome P450 3A4. In this study, we investigated the influence of granisetron on the pharmacokinetics and pharmacodynamics of docetaxel in Asian patients with lung cancer.


METHODS
Six patients with advanced lung cancer were treated with doses of docetaxel (60 mg/m2). In the first course of treatment, no antiemetic agents were administered. In the second course, all patients received 3.0 mg of granisetron before 30-minute administration of docetaxel. In each of the treatment courses, blood samples (5 mL) were obtained for pharmacokinetic study at the following times: 0, 0.5, 1.5, 2.0, 3.0, 5.0, 8.0, and 24 hours after the start of the docetaxel infusion.


RESULTS
Six patients were enrolled in this pharmacokinetics study. The mean +/- SD systemic clearance of docetaxel administered alone or in combination with granisetron was 32.9 +/ - 8.3 and 28.2 +/- 5.9, respectively. The area under the concentration-versus-time curve of plasma docetaxel (alone or in combination with granisetron) ranged from 1.355 to 2.773 and 1.647 to 3.079 microg x h/mL (mean +/- SD: 1.936 +/- 0.541 and 2.219 +/- 0.510 microg x h/mL), respectively. There was no significant difference in mean residence time (or invariance of residence time) between the single dose of docetaxel and the combination of docetaxel and granisetron.


CONCLUSIONS
We found no significant difference in the pharmacokinetic and pharmacodynamic parameters of docetaxel between the single dose of docetaxel and the combination of docetaxel and granisetron. However, a wide interindividual variation existed in cytochrome P450 3A4 activity. It is clear that the results of the present study should be confirmed in a population study involving a larger number of subjects addressing the genetic variations of drug metabolizing enzymes, drug receptors, and drug transporters.
Miyata
Masanori
M
Division of Medical Oncology and Molecular Respirology, Department of Multidisciplinary Internal Medicine, Faculty of Medicine, Tottori University, Yonago, Japan.
Yasuda
Kazuhito
K
Burioka
Naoto
N
Takane
Hiroshi
H
Suyama
Hisashi
H
Shigeoka
Yasushi
Y
Endo
Masahiro
M
Kurai
Jun
J
Morita
Masato
M
Igishi
Tadashi
T
Shimizu
Eiji
E
D000328:Adult; D000368:Aged; D000932:Antiemetics / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics*; D019540:Area Under Curve; D044466:Asian People; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System; D000077143:Docetaxel; D004347:Drug Interactions; D017829:Granisetron / Q000494:pharmacology*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D012702:Serotonin Antagonists / Q000494:pharmacology*; D043823:Taxoids / Q000493:pharmacokinetics*
D000932:Antiemetics; D000972:Antineoplastic Agents, Phytogenic; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System; D000077143:Docetaxel; D017829:Granisetron; D012702:Serotonin Antagonists; D043823:Taxoids; C510163:CYP3A4 protein, human