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Abstract
1. The in vivo metabolism of the antineoplastic and immunosuppressive drug 2-CdA (Leustatin®) was investigated in mice, monkeys and humans after a single subcutaneous dose of cladribine 60 mg kg−1 to eight male and eight female mice and 10 mg kg−1 to one male and one female monkey, and an intravenous infusion dose of cladribine 22–45 mg−1 per subject to 12 male patients.
2. Plasma (1 h), red blood cells (1 h) and faecal samples (0–24 h) were obtained from mice and monkeys, and urine samples (0–24 h) were obtained from these species and humans.
3. Unchanged cladribine (urine: 47% of the sample in human; 60% of the sample in mouse; 73% of the sample in monkey) and 10 metabolites, consisting of four phase I metabolites (M1–3, M7) and six phase II metabolites—five glucuronides (M4, M6, M8–10) and one sulfate (M5) — were profiled, characterized and tentatively identified in plasma, red blood cells, and faecal and urine samples on the basis of API ionspray-mass spectrometry (MS) and MS/MS data.
4. Metabolites were formed via the following three metabolic pathways: oxidative cleavage at the adenosine and deoxyribose linkage (A); oxidation at adenosine/deoxyribose (B); and conjugation (C).
5. Pathways A and B appear to be major steps, forming four oxidative/cleavage metabolites (M1–3, M7) (each 3–20% of the sample).
6. Pathway C along or in conjunction with pathways A and B produced cladribine glucuronide, cladribine sulfate and four glucuronides of oxidative/cleavage metabolites in minor/trace quantities (each ≤ 5% of the sample).
7. In addition, the in vitro metabolism of cladribine was conducted using rat and human liver microsomal fractions in the presence of an β-nicotinamide adenine dinucleotide phosphate-generating system. Unchanged cladribine (≥ 90% of the sample) plus three minor metabolites, M1–3 (each < 8% of the sample), were profiled and tentatively identified by thin-layer chromatography and MS data.
8. Cladribine is not extensively metabolized in vitro and in vivo in all species. However, humans appear to metabolize cladribine to a greater extent than other animals.