Relationship between cladribine (CdA) plasma, intracellular CdA-5'-triphosphate (CdATP) concentration, deoxycytidine kinase (dCK), and chemotherapeutic activity in chronic lymphocytic leukemia (CLL).
Seventeen patients with CLL were treated with oral 2-chloro-2'-deoxyadenosine (cladribine, CdA, 10 mg/m2) on 3 consecutive days and the pharmacokinetic parameters of CdA in patient plasma and its intracellular nucleotides (CdAMP, CdATP) in circulating leukemic cells were studied after the last dose intake and up to 72 h thereafter. The median terminal half life (t1/2) of CdA in plasma was 21.1 h and the area under the curve (AUC) was median 1.2 microMh. The median t1/2 was 14.6 h for CdAMP and 9.7 h for CdATP. The AUC of CdATP in leukemic cells is lower than the AUC of CdAMP (median ratio 0.60). There was no correlation between cellular CdATP and plasma CdA concentrations or dCK activity. The clinical response was related to higher Cmax values for plasma CdA (p = 0.05) and higher products of dCK activity and CdA Cmax of plasma (p = 0.02). The activity of dCK alone was not related to the clinical outcome in this patient group. The results suggest that further steps in the mechanism of action of CdA beyond its bioactivation may be more important, e.g. the extent of DNA fragmentation or the ability of the leukemic cell to go into apoptosis, than the concentration of CdA nucleotides alone.
Albertioni
F
F
Department of Clinical Pharmacology, Karolinska Hospital, Stockholm, Veterinary Medical Chemistry, Linköping, Sweden.
Lindemalm
S
S
Eriksson
S
S
Juliusson
G
G
Liliemark
J
J
D000227:Adenine Nucleotides / Q000097:blood; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000097:blood; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D017338:Cladribine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003842:Deoxycytidine Kinase / Q000378:metabolism*; D005260:Female; D006207:Half-Life; D006801:Humans; D007700:Kinetics; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D016896:Treatment Outcome
D000227:Adenine Nucleotides; D000970:Antineoplastic Agents; C097601:cladribine triphosphate; D017338:Cladribine; D000255:Adenosine Triphosphate; D003842:Deoxycytidine Kinase