Significance of urinary glucaric acid measurement and its application to paclitaxel therapy.
Individual variations in P-450 activity affect the in vivo pharmacokinetics as well as the efficacy and side effect of drugs. It is proposed that urinary glucaric acid (GA) level may indirectly represent P-450 activity and may therefore be an indicator of P- 450 activity in the clinical setting. However, no standard method has been developed so far. Metabolism of paclitaxel (PTX), an anticancer drug, is mediated by P-450. If P-450 activity could be predicted by measuring urinary GA level during PTX administration and individual blood PTX concentration could be inferred, urinary GA level would be a potent tool to predict the efficacy and side effects of the drug. We therefore measured the urinary GA levels of patients on antiepileptics that are suggested to induce P-450 and those of control subjects, to determine whether urinary GA level could be an indicator of P-450 activity. Then, we examined the relationship between urinary GA level and blood PTX concentration and looked into the possibility of predicting pharmacokinetics based on the relationship between urinary GA level and area under the blood concentration-time curve (AUC). The means+/-S. D. of urinary [(GA level)/(Cr level) x 10] levels of 16 patients on antiepileptic medication and 24 control subjects were 0. 98 mg/mL+/-0. 91 and 0. 19 mg/mL+/-0. 07, respectively. The urinary GA levels of patients on antiepileptic medication were significantly higher than those of control subjects. On the other hand, the relationship between AUC and urinary GA levels in eight patients on PTX showed that AUC tended to become large when urinary GA levels were low. The above results reveal that measuring urinary GA level by the easy and noninvasive way of urine collection would enable us to predict P-450 activity and infer blood PTX concentration.
Morimoto
Shigefumi
S
Dept. of Pharmacy, Osaka Minami Medical Center, National Hospital Organization.
Koda
Toshiki
T
Suidzu
Tomoki
T
Uranishi
Ryunosuke
R
Shono
Yoshiharu
Y
Akiyama
Isao
I
Shimizu
Kumiyo
K
Fujita
Yoshikazu
Y
Hasegawa
Kenji
K
Tabuse
Katsuyoshi
K
D000368:Aged; D000927:Anticonvulsants / Q000493:pharmacokinetics; D000972:Antineoplastic Agents, Phytogenic / Q000097:blood / Q000493:pharmacokinetics*; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology; D005260:Female; D005937:Glucaric Acid / Q000652:urine*; D006801:Humans; D008297:Male; D008875:Middle Aged; D017239:Paclitaxel / Q000097:blood / Q000493:pharmacokinetics*
D000927:Anticonvulsants; D000972:Antineoplastic Agents, Phytogenic; D003577:Cytochrome P-450 Enzyme System; D017239:Paclitaxel; D005937:Glucaric Acid