Pharmacokinetics, distribution, and metabolism of the novel bioreductive alkylating indoloquinone EO9 in rodents.
The indoloquinone EO9 is a novel and potent bioreductive agent related in structure to mitomycin C but differing in many aspects of its antitumor activity, toxicity, and enzymatic activation. Because it is about to undergo clinical trial, we have investigated the pharmacokinetics of EO9 in mice and rats. At the highest tolerated dose in male C3H/He mice (12 mg/kg iv) the initial plasma concentration (Co) was 1.8 micrograms/ml. The drug was cleared rapidly with a t1/2 of 1.9 min. The volume of distribution (Vd) was large (7.5 ml g-1) and the plasma clearance (Clp) correspondingly high (2.6 ml g-1 min-1). The AUCo-infinity was 4.8 micrograms ml-1 min. Equally rapid elimination was noted at the lower dose of 6 mg/kg iv. For comparison, the t1/2 for the same dose of mitomycin C was much longer at 16 min and the peak plasma level 4-fold higher. In male Sprague-Dawley rats receiving 3 mg kg-1 the Co was 1.5 micrograms/ml and the t1/2 was again short at 3.0 min. Vd was 2.2 ml g-1, Clp was 0.5 ml g-1 min-1, and AUCo-infinity was 6.2 micrograms ml-1 min. No parent drug was detected in urine, but extensive biotransformation was confirmed by the detection of around 20% of the dose as metabolites, including the aziridine ring-opened hydrolysis product EO5A. No drug or metabolite was detected in tumor or tissues. The results show that cytotoxic drug levels can be achieved for a short period in rodent plasma. The extremely fast excretion is consistent with the rapid rates of bioreductive metabolism in vitro. These data should be useful in the forthcoming clinical trials of EO9, where a pharmacokinetically guided dose escalation may be used, and also in the design and development of second generation analogues.
Workman
P
P
MRC Clinical Oncology and Radiotherapeutics Unit, Cambridge, UK.
Binger
M
M
Kooistra
K L
KL
D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics*; D001388:Aziridines / Q000097:blood / Q000493:pharmacokinetics*; D015687:Cell Hypoxia; D045563:Indolequinones; D007211:Indoles / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D011355:Prodrugs / Q000493:pharmacokinetics*; D051381:Rats; D011919:Rats, Inbred Strains; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D001388:Aziridines; D045563:Indolequinones; D007211:Indoles; D011355:Prodrugs; C060817:apaziquone