Relationships between body composition parameters and fluorouracil pharmacokinetics.
OBJECTIVE
To verify whether fluorouracil (FU) clearance (CL) and volume of distribution (V(ss)) are better correlated with specific body compartments, such as body cell mass (BCM), total body water (TBW) or fat free mass (FFM), rather than with body surface area (BSA) or total body weight (BW).


METHODS
Thirty-four patients (13 females and 21 males) affected by colorectal cancer and receiving FU as adjuvant therapy entered the study. CL and Vss were determined after a 2 min i.v. injection of FU (425 mg m(-2)) and leucovorin (20 mg m(-2)). Body composition, in terms of BCM, TBW and FFM, was evaluated non-invasively by bioelectrical impedance analysis (BIA).


RESULTS
Significant but poor correlations were found between CL or V(ss) and most anthropometric parameters, including BIA-derived measures (r2 range=0.10-0.21). However, when multiple regression analysis was performed with sex, TBW and FFM as independent variables, the correlations improved greatly. The best correlation was obtained between CL and sex (r2=0.44) and between V(ss) and sex (r2=0.36). FFM-normalized CL was significantly higher in women than in men (0.030+/-0.008 vs 0.022+/-0.005 l min(-1) kg)(-1); 95% CI of difference 0.012, 0.003; P=0.003), suggesting that FU metabolism is more rapid in females. Surprisingly, V(ss) was highly correlated with CL (r2=0.67; CL=0.52+V(ss) x 0.040). This finding may either be explained by extensive drug metabolism in extra-hepatic organs or by variable inactivation on first-pass through the lung. Both these hypotheses need experimental validation.


CONCLUSIONS
The pharmacokinetics of FU are better predicted by FFM and TBW than by standard anthropometric parameters and predictions are sex-dependent. The use of BIA may lead to improved dosing with FU.
Department of Pharmacology and Anaesthesiology, University of Padova, Padova and Oncology Division, Rovigo Hospital, Rovigo, Italy.
Milena
M
Gusella
Sivia
S
Toso
Eros
E
Ferrazzi
Mariano
M
Ferrari
Roberto
R
Padrini
D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001823:Body Composition / Q000502:physiology*; D001830:Body Surface Area; D001834:Body Water / Q000378:metabolism*; D001835:Body Weight / Q000502:physiology; D015179:Colorectal Neoplasms / Q000188:drug therapy; D017097:Electric Impedance; D005260:Female; D005472:Fluorouracil / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006801:Humans; D002955:Leucovorin / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D012737:Sex Factors
D000964:Antimetabolites, Antineoplastic; D002955:Leucovorin; D005472:Fluorouracil