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Pharmacokinetics of the Protein Antitumor Antibiotic Neocarzinostatin after Bolus Injection in Humans¹

Section of Oncology, Department of Medicine, SUNY-Upstate Medical Center, Syracuse, New York 13210 [R.L.C., S.J.G.], and Sidney Farber Cancer Institute, Boston, Massachusetts 02142 [T.W.G., V.R.]

Neocarzinostatin is a polypeptide antitumor antibiotic consisting of 109 amino acids (M.W. 10,700) isolated from the culture filtrate broth of Streptomyces carzinostaticus. The pharmacokinetics of neocarzinostatin after bolus injection was examined using a sensitive and specific radioimmunoassay. The pharmacokinetics are described by a two-compartment open model. The drug has a very rapid distribution half-life (t_1/2) of 10.5 ± 5 (S.D.) min which is unaffected by variations in renal function. The elimination half-life (t_1/2ß) is significantly affected by variations in renal function. The mean t_1/2ß for patients with creatinine clearances >40 ml/min was 73 ± 30 min, whereas the t_1/2ß was significantly prolonged, 221 ± 78 min, in patients with creatinine clearances <40 ml/min. Immunochemically intact drug is rapidly and totally excreted in the urine. Although there is a significant delay in urinary excretion for the first 12 hr after drug administration in patients with creatinine clearances <40 ml/min, there is no statistically significant difference in the total amount of drug excreted in 24 hr when patients with creatinine clearances >40 ml/min are compared to those with creatinine clearances <40 ml/min, 107 ± 7% versus 85 ± 28%, respectively. Glomerular filtration appears to be the primary mechanism of renal excretion. No significant protein binding or degradation was noted when radiolabeled neocarzinostatin was incubated in vitro with normal human serum for 4 hr at 37°. The volume of central compartment (V₁) is 4 ± 1 liters, approximating the plasma volume. The apparent volume of distribution (V_D) is 11.8 ± 3 liters, 16 ± 6% body weight, and V_D is not affected by variations in renal function. Neocarzinostatin could not be detected in the bile of one patient or in intracavitary effusions of three patients after bolus injection. No significant hepatic extraction was apparent in one patient when simultaneous hepatic arterial and venous serum samples were examined.

¹ Supported in part by NIH Biomedical Research Support Grant 5S07RR05402-17.

Received 8/14/78. Accepted 11/21/78.