Paradoxical relationship between acetylator phenotype and amonafide toxicity.
Patients receiving the investigational antineoplastic agent amonafide underwent prospective determination of acetylator phenotype with use of caffeine as a test drug. Fast acetylators of caffeine had significantly greater toxicity (myelosuppression) after amonafide treatment than slow acetylators, presumably because of greater conversion of amonafide to the active acetylated metabolite. Furthermore, the estimated area under the plasma concentration-time curve of amonafide was significantly greater in the fast acetylators, indicating that the total plasma clearance was paradoxically lower in this group. It is hypothesized that this paradox is attributable to competition for oxidation of amonafide by its acetylated metabolite (parallel pathway interaction). Pretreatment white blood count and patient age were also independent predictors of leukopenia. In addition, it was noted that the ratio of actual to ideal body weight was significantly higher in the fast acetylators. Studies are in progress to determine the optimal amonafide dose in both acetylator subgroups.
Department of Medicine, University of Chicago Pritzker School of Medicine, IL.
M J
MJ
Ratain
R
R
Mick
F
F
Berezin
L
L
Janisch
R L
RL
Schilsky
S F
SF
Williams
J
J
Smiddy
D000107:Acetylation; D000225:Adenine; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000493:pharmacokinetics; D001835:Body Weight; D005260:Female; D006801:Humans; D007094:Imides; D007546:Isoquinolines / Q000009:adverse effects* / Q000493:pharmacokinetics; D007970:Leukopenia / Q000139:chemically induced*; D008297:Male; D008875:Middle Aged; D053644:Naphthalimides; D063065:Organophosphonates; D010641:Phenotype; D011446:Prospective Studies
D000970:Antineoplastic Agents; D007094:Imides; D007546:Isoquinolines; D053644:Naphthalimides; D063065:Organophosphonates; C037020:amonafide; D000225:Adenine