Pharmacokinetics of Chlorambucil in Patients with Chronic Lymphocytic Leukaemia: Comparison of Different Days, Cycles and Doses

Abstract

The effects of repeated treatment cycles and different doses on intraindividual variation in oral bioavailability of chlorambucil and its first, active, and more toxic metabolite, phenylacetic acid mustard, were studied. Chlorambucil and phenylacetic acid mustard concentrations were measured with HPLC on Day 1 and on Day 4 in 15 timed blood samples from 11 chronic lymphocytic leukaemia patients receiving chlorambucil therapy cycles. Bioavailability was evaluated also after the first chlorambucil doses of six consecutive treatment cycles repeated every 4 weeks with increasing chlorambucil doses starting with 0.8 mg/kg/4 days, and increased by 0.1 mg/kg/4 days cycle. Area under the concentrationtime-curve (AUC) from tΩ0 to infinite was in average 3.2 hr*mg/ml for the first cycle, and decreased by 17% in four days (PϽ0.05). The mean distribution half-life of chlorambucil was 0.49 hr and the terminal elimination half-life 2.45 hr. The bioavailability of chlorambucil decreased further when 4-day treatment cycles were repeated. For the fifth cycle, dosecorrected AUC for the first 2 hr was 33% smaller than that for the first cycle (P for trend Ͻ0

Prospective trial of metronomic chlorambucil chemotherapy in dogs with naturally occurring cancer

“…Chlorambucil has also been used in dogs with lymphoma and myeloma 25,26 . The pharmacokinetics and dosing of chlorambucil in humans and laboratory animals have been reported 27–32 . Although less has been reported concerning the pharmacokinetics of chlorambucil in dogs, the drug has been used in dogs for more than 25 years, with dosages up to 8 mg m −2 being used.…”

The Nitrogen Mustards

“…Chlorambucil and its active more toxic metabolite phenylacetic acid mustard have been quantified using HPLC in patients with CLL (Silvennoinen et al, 2000). The internal standard was N, N-diethyl-m-toluamide.…”

Διερεύνηση Των Μηχανισμών Με Τους Οποίους Χημικές Ενώσεις Με Αντινεοπλασματικές Ιδιότητες Προκαλούν Γενετικές Ανωμαλίες

“…Εικόνα 3.5.: Χηµική δοµή PHE Ο µεταβολισµός της χλωραµ̟ουκίλης έχει βρεθεί ότι δεν ακολουθεί γραµµική σχέση, ό̟ως ̟ροέκυψε α̟ό µελέτη ̟ου αφορούσε τη φαρµακοκινητική του φαρµάκου σε ασθενείς µε χρόνια λεµφογενή λευχαιµία (Silvennoinen et al, 2000). Σε ένα ̟ρώτο στάδιο µετά τη χορήγηση του φαρµάκου εµφανίζεται µεγάλη συγκέντρωση του PHE στο ̟λάσµα, η ο̟οία ακολουθεί µία έντονη µείωση.…”