The alkylating activity in the urine was measured in patients receiving a new antineoplastic cyclophosphomide analog, isophosphamide (IP), at doses of 2,900 to 5,000 mg per square meter body surface area (BSA) and compared with that of patients receiving 1,100 mg per square meter of cyclophosphamide (CP). Total excretion of alkylating activity after CP (1,l00 mg per square meter) lay between values for the 3,800 mg per square meter dose and the 5,000 mg per square meter dose of IP. The concentration of urinary alkylating activity was higher in patients who developed cystitis than in those who did not. Alkylating activity in the urine was unaltered by acetylcysteine bladder washout. Plasma alkylating activity was more persistent after 5,000 mg per square meter IP than after 1,100 mg per square meter CPo After [HC] IP 5,000 mg per square meter, the plasma half-life was 13.79 hours, and the urinary recovery of radioactivity was 81.6%, of which 61.6% was unchanged drug. These values differ markedly from those published for CPo IP penetrated the blood-brain barrier, but its metabolites did not. The greater propensity of IP than of CP to cause cystitis at apprOXimately equitoxic doses may be related to larger amounts of alkylating activity in urine of patients receiving [P. The greater dose of IP than of CP required to produce the same alkylating activity in urine correlates well with the differences in Km of the two drugs in an isolated microsomal enzyme system in vitro previously reported.

where: V = organ wet weight. g, C = concentration, ug g (or ml). t = time. min, Q = flow rate, ml/min, R = tissue-to-plasma equilibrium, distribution ratio, k = clearance, ml/min.The subscript K and P refer respectivelv to kidnev and plasma. The model has been used to predict concentrations in tissues in man after intravenous Mtx from the plasma concentration data of Henderson, Adamson and Oliverio (1965). Since it is an important part of the function of a pharmacokinetic model to predict for data that are important to, but not readily obtainable bv, the clinician using the drug it is essential to determine as far as possible how far the predictions of the model match with subsequently obtained data. We recently studied liver biopsy specimens in 4 patients, 3 at 3 hours and 1 at 24 hours after intravenous [3H] Mtx, and bile from another patient who had a complete biliarv fistula and we were able to compare observed values for hepatic and biliarv Mtx levels with those predicted by the model. The model predicts a liver to plasma ratio of approximately 5: 1 and preferential biliarv excretion of drug.All patients had inoperable cancer that was not amenable to conventional therapy and were entering a study of the clinical evaluation of Mtx (Selawrv, 1970); all gave informed consent to entry into the study. All had normal renal function as defined by a blood urea nitrogen level of <25 mg/100 ml and serum creatinine con-* Present address: Petersborgvej 21, 3400 Hillerod, Denmark.

The bioavailability of the antineoplastic agent, ICRF-159, has been examined in 12 patients receiving the drug in single and subdivided dose schedules in an attempt to account for the differences in toxicity found with the different schedules clinically. Recovery of radioactivity in the urine after single large doses (13.3-19.4 g) was 8.5 +/- 3.0% of the administered dose. After doses of 3.8-5.55 g recovery was 22.7 +/- 10.5% and after the same dose subdivided into 3 equal aliquots it was 52 +/- 8.7%. Unrecovered radioactivity was largely accounted for in the faeces. Plasma radioactivity levels in 2 patients after high and low dose were equivalent. Toxicity of the drug paralleled urinary recovery of radioactivity. It is concluded that schedule dependence of toxicity of ICRF-159 is at least partly due to bioavailability factors.

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Summary. DEAE‐Sephadex column chromatography has been used to study the haemoglobins of AKR untreated mice, polycythaemic mice injected with saline and polycythaemic mice treated with an extract of human erythropoietin. All elution patterns of the haemolysates showed four haemoglobins. The haemolysates of each group had an elution pattern different from the other groups. Chromatographic studies of an ageing haemolysate indicated the formation of a minor haemoglobin from a major haemoglobin to be linear for a period of about 18 days. The major AKR mouse haemoglobin appeared to polymerize, possibly to octaniers. Human erythropoietin, when injected into polycythaemic mice, seemed to decrease the resulting polymerization of the major haemoglobin and the formation of the minor haemoglobin. Treatment of the haemolysates with reduced glutathione seemed to depolymerize the polymers to tetramers. An extract of human erythropoietin lowered the glutathione level in the blood of an AKR strain of mice.