Pharmacokinetics of intraarterial mitomycin C in hypoxic hepatic infusion with embolization in the treatment of liver metastases.
1. The pharmacokinetics of mitomycin C (MMC) was evaluated during hypoxic hepatic infusion (HHMI) with arterial embolization for the treatment of unresectable liver metastases. 2. Ten patients with hepatic metastases from colorectal cancer were considered. Antiblastic infusion with MMC (20 mg/m2 at 30 ml/min) was initiated after 10 min of hepatic arterial occlusion. Peripheral venous blood samples were collected at different time intervals. MMC was assayed by high-pressure liquid chromatography (HPLC), and pharmacokinetic parameters were determined using an open, two-compartment model and linear kinetics. 3. Cmax of MMC during HHMI was 708 +/- 336.6 ng/ml, and tmax was 9.3 +/- 1.1 min. The plasma concentration-time curve showed a t1/2 alpha ranging from 1.5 to 9 min, followed by a t1/2 beta ranging from 31 to 93 min. The Cltot was 35.5 l/h/m2 with an area under the plasma concentration-time curve (AUC) ranging from 251 to 850 micrograms h/l. The same AUC parameter standardized for the amount of MMC was 15.5 mg-1. The HHMI model that we used revealed a significant increase in Cltot and a reduction in AUC when compared to the locoregional intraarterial and peripheral intravenous models (p < .001). 4. The reduction in AUC following HHMI explains the limited systemic toxicity in treated patients, with a greater total tumor exposure to the drug and improved drug activation.
Cerretani
Daniela
D
Department of Pharmacology G. Segre, University of Siena, Via delle Scotte 6, 53100 Siena, Italy.
Roviello
Franco
F
Pieraccini
Massimo
M
Civeli
Letizia
L
Correale
Pierpaolo
P
Francini
Guido
G
Marrelli
Daniele
D
De Manzoni
Giovanni
G
Pinto
Enrico
E
Giorgi
Giorgio
G
D000328:Adult; D000368:Aged; D019540:Area Under Curve; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000556:secondary; D004621:Embolization, Therapeutic / Q000379:methods*; D005260:Female; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D007261:Infusions, Intra-Arterial / Q000379:methods*; D016018:Least-Squares Analysis; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000556:secondary; D008297:Male; D008875:Middle Aged; D016685:Mitomycin / Q000008:administration & dosage / Q000493:pharmacokinetics*
D016685:Mitomycin