A human capecitabine excretion balance and pharmacokinetic study after administration of a single oral dose of 14C-labelled drug

Abstract

An excretion balance and pharmacokinetic study was conducted in cancer patients with solid tumors who received a single oral dose of capecitabine of 2000 mg including 50 microCi of 14C-radiolabelled capecitabine. Blood, urine and fecal samples were collected until radioactive counts had fallen to below 50 dpm/mL in urine, and levels of intact drug and its metabolites were measured in plasma and urine by LC/MS-MS (mass spectrometry) and 19F-NMR (nuclear magnetic resonance) respectively. Based on the results of the 6 eligible patients enrolled, the dose was almost completely recovered in the urine (mean 95.5%, range 86-104% based on radioactivity measurements) over a period of 7 days after drug administration. Of this, 84% (range 71-95) was recovered in the first 12 hours. Over this time period, 2.64% (0.69-7.0) was collected in the feces. Over a collection period of 24-48 h, a total of 84.2% (range 80-95) was recovered in the urine as the sum of the parent drug and measured metabolites (5'-DFCR, 5'-DFUR, 5-FU, FUH2, FUPA, FBAL). Based on the radioactivity measurements of drug-related material, absorption is rapid (tmax 0.25-1.5 hours) followed by a rapid biphasic decline. The parent drug is rapidly converted to 5-FU, which is present in low levels due to the rapid metabolism to FBAL, which has the longest half-life. There is a good correlation between the levels of radioactivity in the plasma and the levels of intact drug and the metabolites, suggesting that these represent the most abundant metabolites of capecitabine. The absorption of capecitabine is rapid and almost complete. The excretion of the intact drug and its metabolites is rapid and almost exclusively in the urine.

Fluorine-19 or phosphorus-31 NMR spectroscopy: A suitable analytical technique for quantitative in vitro metabolic studies of fluorinated or phosphorylated drugs

“…The mean value for the urinary recovery of drug and its metabolites up to 48 h post-dosing, measured by 19 F NMR (84.2%), is in agreement (within 10%) with the 92.3% of the radioactivity recovered at that time, demonstrating the reliability of the 19 F NMR spectroscopic quantification [62]. Moreover, all the metabolites of the catabolic pathway: CAP → 5 dFCR → 5 dFUR → FU → FUH 2 → FUPA → FBAL (Fig.…”

“…Moreover, all the metabolites of the catabolic pathway: CAP → 5 dFCR → 5 dFUR → FU → FUH 2 → FUPA → FBAL (Fig. 4) are quantified [62,63]. As expected, the major metabolite by far is FBAL, with 5 dFCR, 5 dFUR and FUPA the other significant forms, FU and FUH 2 representing a small percentage of the excretion (Table 2).…”

“…Indeed about 98% of a single 2 g oral dose of radiolabelled CAP is recovered over a period of 6 days based on radioactivity measurements (95.5% in urine and 2.6% in faeces) with a very large proportion (84%) excreted in urine in the first 12 h post-dosing [62].…”

Simple determination of capecitabine and its metabolites by liquid chromatography with ultraviolet detection in a single injection

“…1). Following rapid and almost complete absorption of the intact molecule from the gastrointestinal tract [9], capecitabine becomes effective after selective conversion of its major metabolites 5 -deoxy-5-fluorocytidine (5 -DFCR) and 5 -deoxy-5-fluorouridine (5 -DFUR or doxifluridine) to 5-FU within human cancer cells. It is converted to 5 -deoxy-5-fluorocytidine (5 -DFCR) by the hepatic enzyme, carboxylesterase.…”

“…Capecitabine is rapidly and almost completly absorbed and converted to its metabolites following the oral administration of single doses in cancer patients [9,[14][15][16]. The peak plasma concentration for the drug and its metabolites 5 -DFCR, 5 -DFUR and 5-FU occurs shortly (median t max 2.0 h) after oral administration and its elimination half life was approximately 1 h [17].…”