Hepatotoxicity of cyclophosphamide in man: pharmacokinetic analysis.
Of 44 patients with neoplasia treated with cyclophosphamide (CPA), 19 (43%) had a transient elevation of serum levels of aminotransferases. In these patients, regardless of the combination chemotherapy regimen given, the incidence of liver dysfunction was 33%, when the total CPA dose was less than 400 mg/m2 (Group A) and 73% with higher doses (Group B). Prior to the initiation of CPA treatment, pharmacokinetics of CPA were investigated in 15 patients. Plasma AUCs of CPA and phosphoramide mustard (PM) in 8 patients in Group B were higher than those in 7 Group A patients. In contrast, urinary excretion of 3-hydroxypropyl-mercapturic acid (3-HPMCA) was lower in Group B than in Group A. The ratio of urinary 3-HPMCA to plasma AUC of PM was significantly lower in Group B than in Group A (p less than 0.05). These results indicate that CPA-induced liver injury is mainly dose-dependent and presumably results from impaired metabolism of CPA, and especially of its metabolite, acrolein.
Honjo
I
I
Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Japan.
Suou
T
T
Hirayama
C
C
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D056486:Chemical and Drug Induced Liver Injury / Q000139:chemically induced / Q000209:etiology; D002648:Child; D003520:Cyclophosphamide / Q000009:adverse effects* / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D008099:Liver / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D000637:Transaminases / Q000097:blood
D003520:Cyclophosphamide; D000637:Transaminases