Relationships between body composition parameters and fluorouracil pharmacokinetics

Department of Pharmacology and Anaesthesiology and Department of Clinical and Experimental Medicine, University of Padova, Padova and Oncology Division, Rovigo Hospital, Rovigo, Italy

Correspondence: Roberto Padrini, Dipartimento di Farmacologia e Anestesiologia, Largo Meneghetti 2, 35131 Padova, Italy. Tel.: +39-049-8275777; Fax:+39-049-8275093; E-mail: ti.dpinu@inirdap.otrebor

Department of Pharmacology and Anaesthesiology and Department of Clinical and Experimental Medicine, University of Padova, Padova and Oncology Division, Rovigo Hospital, Rovigo, Italy

Received 2001 Jun 5; Accepted 2002 Mar 4.

Abstract

Aims

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 V_ss were determined after a 2 min i.v. injection of FU (425 mg m^{) and leucovorin (20 mg m}^{). 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 (r^{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 (}r^{= 0.44) and between}V_ss and sex (r^{= 0.36). FFM-normalized CL was significantly higher in women than in men (0.030 ± 0.008}vs 0.022 ± 0.005 l min^kg^{; 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 (r^{= 0.67; CL = 0.52 +}V_ss × 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.

Keywords: bioelectrical impedance analysis, fluorouracil, pharmacokinetics

Abstract

BW = body weight; BSA = body surface area; R = resistance; Xc = reactance; TBW = total body water; FFM = fat free mass; BCM = body cell mass.

Abbreviations as in Table 1.

Acknowledgments

This work was supported by grants from the Regione Veneto (ricerca finalizzata n°934/02/99) and University of Padova (fondi ex-60%, area del farmaco).

Acknowledgments

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