Dexamethasone as a probe for CYP3A4 metabolism: evidence of gender effect.
BACKGROUND
A study was conducted to evaluate prospectively the correlation between docetaxel clearance and pharmacokinetics of dexamethasone previously obtained in 21 patients.


METHODS
Dexamethasone pharmacokinetics were performed in 17 patients 24 h before docetaxel treatment as monochemotherapy. Dexamethasone and docetaxel plasma concentrations were determined by HPLC methods. Determination of docetaxel unbound fraction in plasma was performed using microequilibrium dialysis.


RESULTS
Significant correlation was observed between observed plasma docetaxel clearances (CL(docetaxel)) and values predicted from dexamethasone plasma clearance (CL(dexa)), unbound plasma docetaxel fraction estimated from serum alpha1-acid glycoprotein level (fu(alpha1-AAG)), and hepatic metastasis status. However, after splitting of the prospective data set according to gender, no correlation was observed for males (R(2) = 0.08, NS, n = 10), then strong correlation was observed for females (R(2) = 0.78, P < 0.01, n = 7). Multivariate analysis was performed from data obtained in the women included in the first study and those of this prospective study (n = 18). Docetaxel CL was significantly correlated with CL(dexa) (P = 0.001) and fu(alpha1-AAG) (P = 0.01) according to the relationship (with +/-95% confidence intervals): CL(docetaxel) (l/h) = 1.92 (+/-0.94) x CL(dexa) (l/h) + 2.68 (+/-1.95) x fu(alpha1-AAG) (%) (R(2) = 0.68).


CONCLUSIONS
Dexamethasone may be used to predict docetaxel clearances in females, but not in males.
Puisset
F
F
EA3035, Institut Claudius-Regaud, 31000 Toulouse, France.
Chatelut
E
E
Sparreboom
A
A
Delord
J-P
JP
Berchery
D
D
Lochon
I
I
Lafont
T
T
Roché
H
H
D000328:Adult; D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003907:Dexamethasone / Q000493:pharmacokinetics*; D000077143:Docetaxel; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D011446:Prospective Studies; D012737:Sex Factors; D043823:Taxoids / Q000008:administration & dosage / Q000493:pharmacokinetics*
D018931:Antineoplastic Agents, Hormonal; D043823:Taxoids; D000077143:Docetaxel; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human