The effect of carboxylesterase 1 (CES1) polymorphisms on the pharmacokinetics of oseltamivir in humans.
OBJECTIVE
The aim of this study was to examine whether carboxylesterase 1 (CES1A) genetic polymorphisms affect the pharmacokinetics of oseltamivir.


METHODS
Thirty healthy Japanese male and female subjects ranging in age from 20 to 36 years voluntarily participated in this study. These subjects were administered a single 75-mg dose of oseltamivir (Tamiflu®), and blood samples were collected predose and up to 24 h after oseltamivir administration. Oseltamivir and its active metabolite, oseltamivir carboxylate, were measured by liquid chromatography-time of flight/mass spectrometry with solid-phase extraction. The CES1A diplotypes [a combination of haplotypes A (CES1A3-CES1A1), B (CES1A2-CES1A1), C (CES1A3-CES1A1variant), and D (CES1A2-CES1A1variant)] were determined by PCR-restriction fragment length polymorphism analysis and direct sequencing.


RESULTS
All subjects completed the study according to the protocol, and no clinically meaningful adverse events were attributable to the administration of oseltamivir. No significant differences in the pharmacokinetic parameters of oseltamivir and oseltamivir carboxylate were observed according to CES1A genotype. In one subject, the peak concentration and area under the concentration-time curve (AUC) of oseltamivir were approximately tenfold higher than the mean values of the other subjects.


CONCLUSIONS
In our study, the known interindividual variability in oseltamivir metabolism was not explained by CES1A genetic polymorphisms, but are likely the result of other factors. While one subject was found to exhibit an approximate tenfold higher AUC than the other subjects, no abnormal behaviors were associated with the increased oseltamivir plasma concentrations. Further studies are required to reveal the cause of individual differences in CES1A metabolism and the abnormal behavioral effects of oseltamivir.
General Clinical Research Center, Oita University Hospital, 1-1 Idaigaoka, Hasama-machi, Yufu-shi, Oita 879-5593, Japan. ysuzaki@oita-u.ac.jp
Yuki
Y
Suzaki
Naoto
N
Uemura
Makoto
M
Takada
Tetsuji
T
Ohyama
Akiko
A
Itohda
Takuya
T
Morimoto
Hiromitsu
H
Imai
Hajime
H
Hamasaki
Akihiro
A
Inano
Masakiyo
M
Hosokawa
Masato
M
Tateishi
Kyoichi
K
Ohashi
D000328:Adult; D000998:Antiviral Agents / Q000493:pharmacokinetics*; D044466:Asian People / Q000235:genetics; D002265:Carboxylic Ester Hydrolases / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D053139:Oseltamivir / Q000493:pharmacokinetics*; D011110:Polymorphism, Genetic; D055815:Young Adult
D000998:Antiviral Agents; D053139:Oseltamivir; D002265:Carboxylic Ester Hydrolases; C474609:CES1 protein, human