Comparison of the urinary excretion of CP and its metabolites as reported in the literature and in the present study
| Bagley et al. (1973) | Jardine et al. (1978) 5-a | Jarman et al. (1979) 5-a | Hadidi et al. (1988) | Boddyet al. (1992) 5-b | Tasso et al.(1992) 5-a | Chan et al. (1994) | Yule et al. (1995) 5-b | Present Study | ||
|---|---|---|---|---|---|---|---|---|---|---|
| Number of patients | 26 | 3 | 4 | 14 | 17 | 3 | 6 | 6 | 4 | |
| Age (years) | Not reported | 16, 45, 62 | 54–68 | 37–72 | 15–73 | 4, 15, 175-c | Not reported | 3–18 | 37–57 | |
| Dose | 6–80 mg/kg | 60 or 75 mg/kg | 1 g | 0.6–1.8 g/m2 | 100–1080 mg | 0.6–1.5 g/m2 | 1 g/m2 | 557–1500 mg/m2 | 60 mg/kg/day on 2 consecutive days | |
| Administration | <10-min iv infusion | 1-hr iv infusion | iv bolus | 1-hr iv infusion | po or short iv infusion | 1-hr iv infusion | 20-min iv infusion | 1-hr iv infusion | 3-hr iv infusion | |
| Urine sampling | 24 hr | 24 hr | 24 hr | 24 hr | 24 hr | 24 hr | 24 hr | 24 hr | 24 hr after the start of each infusion | |
| Analytical method | Radioactivity and NBP assay5-d | GC/MS/SID5-e | TLC/MS/SID | TLC/PD | TLC/PD | TLC/PD | GC/MS/SID | TLC/PD | 31P NMR | |
| Excretion (%) | Day 1 | Day 2 | ||||||||
| Unmetabolized CP | 11 (3–19)5-f | 20.3 (16.3–25.1) | 5.2 ± 1.7 (3.9–7.6) | 12.7 ± 9.3 (2.8–31.4) | 2.6 ± 1.9 (0.3–6.5) | 18.9 (5.4–43.2) | 10.8 ± 4.2 | 18.3 ± 12.7 (5.4–43.2) | 16.0 ± 3.3 (11.5–20.7) | 14.7 ± 2.5 (11.7–18.2) |
| CXCP | 5.5 ± 1.3 (4.3–7.2) | 3.1 ± 3.7 (0.05–10.1) | 1.9 ± 3.1 (0.01–13.6) | 11.5 (3.4–22.3) | 9.7 ± 6.4 (4.0–22.3) | 11.5 ± 3.0 (7.1–15.5)5-g | 23.2 ± 3.7 (19.9–28.9)5-g | |||
| DCCP | 0.8 ± 0.9 (0.1–4.0) | 1.3 (0.3–3.2) | 3.4 ± 1.8 (0.3–6.0) | 3.4 ± 1.1 (1.8–4.8)5-g | 5.0 ± 1.7 (3.3–6.9)5-g | |||||
| PM | 1.9 (1.2–2.8)5-h | 18.5 ± 16.1 (2.7–52.9)5-h | 3.3 ± 3.7 (0.05–10.9)5-h | 5.5 (0.7–8.5)5-h | 39.0 ± 30.0 | 0.3 ± 0.1 (0.1–0.4) | 0.6 ± 0.2 (0.4–0.7) | |||
| KetoCP | 1.1 ± 0.6 (0.6–1.7) | 1.0 ± 0.9 (0.4–3.9) | 0.4 ± 0.5 (0.02–2.1) | 0.55-i | 0.9 ± 0.8 (0–2.0) | 0.4 ± 0.2 (0.1–0.6) | 0.6 ± 0.2 (0.3–0.8) | |||
| AlcoCP | 0.4 ± 0.4 | 2.3 ± 0.7 (1.1–2.8) | 4.6 ± 0.7 (3.6–5.6) | |||||||
| NNM | 12.0 (10.4–14.5)5-j | 0.8 ± 0.6 (0–2.1)5-k | 3.0 ± 2.0 | |||||||
| Total metabolites | 16 ± 5 (8–23) | 13.9 | 6.6 | 23.4 | 6.4 | 18.5 | 42.95-l | 14.0 | 20.4 ± 4.9 (12.7–26.4)5-m | 37.3 ± 6.2 (30.8–45.4)5-m |
| Total excretion | 62 ± 10 (41–82)5-n | 34.2 (32.6–37.3) | 11.8 | 36.2 ± 17.8 (6.5–64.1) | 9.0 ± 5.7 (1.3–18.8) | 37.4 (12.5–59.7) | 53.75-l | 32.3 ± 9.7 (23.0–52.4) | 36.4 ± 8.2 (24.2–47.2)5-m | 52.0 ± 8.3 (43.5–61.1)5-m |
Data are expressed as percentages (mean ± SD) of the CP-administered dose. Ranges are shown in parentheses.
↵5-a These values are not reported in the paper but were calculated by us from the given data.
↵5-b The values given by the authors were median values; mean ± SD values given here were determined from the data reported in the paper.
↵5-c Urinary recovery was reported only for the three patients receiving CP for the first time in the course of treatment, with administration in a single dose, and for whom urine collection was complete.
↵5-d 14C-labeled CP was determined in the chloroform phase after urine extraction. Total alkylating metabolites were measured by the NBP colorimetric assay in crude urine samples, because CP did not react with NBP.
↵5-e SID, stable isotope dilution; PD, photographic densitometry.
↵5-f Values reported by Sladek (1994).
↵5-g Because CXCP and DCCP are not stable at acidic pH, the amounts of their degradation products were included in the values reported.
↵5-h Yule et al. (1993) subsequently demonstrated that PM was not reliably detected either with methods requiring its derivatization using diazomethane or with the TLC/photographic densitometry method.
↵5-i KetoCP was detected for only one patient.
↵5-j Those authors attributed the high levels of NNM, in part, to decomposition of other metabolites, especially CXCP, during sample preparation and storage.
↵5-k Boddy et al. (1992) subsequently demonstrated that the NNM extraction procedure used was not reproducible and so NNM was not reliably assayed.
↵5-l OHCP was also analyzed. Its amount (0.5 ± 0.5%) was included in the total metabolites excreted value, as well as in the total excretion value.
↵5-m These values included the amounts of 9-OdAP, the CP degradation product, as well as all unidentified CP-related compounds listed as “Others” in table 4.
↵5-n Total radiolabeled excretion in 48 hr.