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 functional morphology of the M. canalis ani is described. Hitherto this muscle has not been studied in detail. The M. canalis ani is located inside of the M. sphincter ani internus and reaches through the spatium submucosum et subcutaneum of the analcanal. This muscle is part of a described "organ of continence". Its importance in the course of anorectal disease is shown.

Individual tolerance to single or widely spaced doses of methotrexate was explored in 49 patients with advanced cancer with normal serum creatinine and/or blood urea nitrogen. Methotrexate was given as an intravenous infusion over 1 hour at initial doses of 80-120 mg./m 2 body surface area. The doses were increased by 50% increments every 2 weeks until moderate toxicity occurred, arbitrarily defined as leukopenia <5000/mm. 3 , and/or thrombocytopenia <100,000/mm. 3 , and/or the appearance of oral mucous or intestinal toxicity. The individual dose required to produce initial evidence of toxicity varied by a factor of 18 between 50 and 900 mg./m 2 . Starting doses above 80 mg./m 2 were potentially hazardous. Dose limiting toxicity consisted of leukopenia with or without stomatitis in 81% of the patients, and stomatitis without leukopenia, in 19%. Thrombocytopenia was seen in 19% of the patients, but was never a dose limiting factor alone. Leukopenia always preceded thrombocytopenia. The nadir for haematologic toxicity varied considerably between day 5-15 and 9-14 for leukocytes and platelets, respectively, while oral ulcerations, when they occurred, consistently began between days 3-6 after drug administration. Other toxic manifestations included dermatologic changes in 8 patients, hepatic dysfunction in 7, conjunctivitis in 7, nausea and vomiting in 6, alopecia in 4, and diarrhea in 3 patients. The only factor which predicted toxicity was the patient's age. Drug tolerance was independent of previous chemotherapy or radiotherapy, weight loss, serum albumin or pretreatment serum folic acid levels.

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