Platinum-DNA adduct formation in leucocytes of children in relation to pharmacokinetics after cisplatin and carboplatin therapy.
Platinum (Pt)-DNA adducts were measured in peripheral blood leucocytes (PBLs) from 24 children with solid tumours after standard cisplatin and/or carboplatin treatment. The relationship between Pt-DNA adduct levels and pharmacokinetics of cisplatin and carboplatin was investigated. Adduct measurements were performed by competitive enzyme-linked immunosorbent assay (ELISA) and plasma unbound Pt concentrations were measured by atomic absorption spectrophotometry (AAS). There was considerable interindividual variation in Pt-DNA adduct level that was weakly correlated (r2 = 0.32) with the area under the unbound drug concentration vs time curve (AUC) at 6 h after the start of cisplatin infusion, indicating that the variation in Pt-DNA adduct levels was primarily determined by factors other than AUC. No clear relationship between AUC and adduct levels was seen at 24 and 48 h after cisplatin or at 6, 24 or 48 h after carboplatin. Carboplatin produced lower levels of immunoreactive adducts than did cisplatin (1.3 +/- 0.6 nmol Pt g-1 DNA vs 3.2 +/- 1.7 nmol Pt g-1 DNA), despite a 20-fold higher unbound drug AUC for carboplatin (8.0 +/- 3.5 mg ml-1 min vs 0.4 +/- 0.2 mg ml-1 min). This study demonstrates that, after cisplatin and carboplatin treatment the drug-target interaction is determined by both pharmacokinetic and, predominantly, cellular factors. Intrinsic differences between the two complexes, primarily reactivity, probably explain the lower adduct levels observed after carboplatin treatment.
Peng
B
B
Department of Oncology, Medical School, The University of Newcastle upon Tyne, UK.
Tilby
M J
MJ
English
M W
MW
Price
L
L
Pearson
A D
AD
Boddy
A V
AV
Newell
D R
DR
D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D016190:Carboplatin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D002945:Cisplatin / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D018736:DNA Adducts / Q000097:blood*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D006801:Humans; D007223:Infant; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009369:Neoplasms / Q000097:blood* / Q000188:drug therapy
D000970:Antineoplastic Agents; D018736:DNA Adducts; C057270:cisplatin-DNA adduct; D016190:Carboplatin; D002945:Cisplatin