No abstract

Daunorubicin (daunomycin, rubidomycin, rubomycin C) 11,20 has been an effective and promising drug in the treatment of acute leukemia. While evaluating the efficacy of daunorubicin therapy in patients with solid tumors, we also studied the pharmacokinetics of daunorubicin and suggested a modification of the treatment schedule. 1 A metabolite, daunorubicinol, was also demonstrated in human plasma and urine; but no efforts were made to quantify metabolite formation. Although daunorubicin is metabolized in vitro to daunorubicinol and to daunorubicin aglycone, daunorubicinol aglycone, deoxydaunorubicin aglycone, and deoxydaunorubi-

The pharmacokinetics of SH‐methotrexate were studied in 22 patients with malignancies. Following the intravenous administration of 30 mg methotrexate (Mtx) per square meter, the plasma disappearance was triphasic with half‐lifes of 0.7.5 ± 0.11,3.49 ± 0 . .55, and 26.99 ± 4.44 hours, respectively. The urinary excretion of radioactivity paralleled the plasma data for most patients. A metabolite was found in urine that eluted before Mix when chromatographed on a diethylaminoethyl (DEAE) cellulose column. The excretion of this metabolite reached steady state and accounted for 20 (14 to 37) per cent of the radioactivity in urine after 30 hours. Our observation that Mtx has a long terminal half‐life may explain the high incidence of tOXicity in patients receiving chronic low‐dose Mtx therapy.

The effect of propranolol on antipyrine clearance in humans was evaluated in six healthy volunteers who received single 1.4 to 1.5 g doses of intravenous antipyrine on two occasions. The first (control) antipyrine trial was without concurrent drug administration; the second trial was done during treatment with therapeutic doses of propranolol (40 mg every 4 to 6 hours). Antipyrine elimination half-life (t1/2), volume of distribution (Vd), and total clearance were determined after each trial. In all subjects isoproterenol sensitivity decreased markedly during propranolol treatment, indicating a high degree of beta blockade produced by the drug. Mean antipyrine t1/2 during the propranolol treatment period was significantly prolonged, and total clearance significantly reduced, over the control values. Twenty-four-hour urinary excretion of 4-hydroxyantipyrine, the major metabolite of antipyrine, likewise was reduced from 23.6% of the dose on the control trial to 14.8% of the dose during propranolol coadministration (0.1 less than P less than 0.2). Vd however, was nearly identical during both trials (0.62 L/kg). Thus propranolol prolongs the half-life and reduces the clearance or biotransformation rate of antipyrine, a drug whose clearance is independent of hepatic blood flow. Propranolol may influence the activity of hepatic microsomal enzymes responsible for drug hydroxylation.