ORALLY ADMINISTERED POLYENE MACROLIDES

effect of orally administered polyene macrolides on steroid levels in the dog was investigated. In preliminary studies it was observed that the oral administration of polyene macrolides to dogs markedly influenced the serum cholesterol levels. These studies were greatly enlarged to determine the effect of a variety of polyene macrolides by the oral route on the serum cholesterol levels of the dog. The results are presented in this report. Materials and Methods.-In these studies a total of 79 purebred beagle dogs (48 males and 31 females), 10-12 months old, weighing approximately 20 pounds were used. The dogs were quarantined for a period of seven days during which time they were stabilized as to diet (Purina dog meal), feeding schedule, and handling. All polyene antifungal antibiotics employed in these studies were assayed for microbiological potency as determined against Saccrhaoromyces cerevisiae ATCC 9763 by a tube dilution procedure.2 The polyene macrolides employed in these studies included candicidin (S. B. Penick, lot 8031-LHO-11, 45%), amphotericin B (E. R. Squibb, lot 38675001, 90.4%), filipin (Upjohn, lot U5956, 96%), and nystatin (E. R. Squibb, lot 36982-013, 4230 units/mg). The compounds were placed in hard gelatin capsules and were administered orally with the normal diet, in divided doses given in the morning and late afternoon. Serum cholesterol levels were determined prior to drug administration. Blood samples were taken daily from the jugular vein on three successive days to determine base line serum cholesterol values. The methods of Leffler3 and Ferro and Ham4 were used in these determinations. After 21 days of successive daily drug administration, the animals were finally bled, and the serum cholesterol levels were again determined. Results.-A summary of the results obtained with the measurement of serum cholesterol levels of dogs after the oral administration of four polyene macrolide antifungal antibiotics is given in Table 1. The heptaene macrolide candicidin' was administered at three dose levels, corresponding approximately to 5, 10, and 20 mg/kg body weight. Some gastrointestinal disturbances were noted in the dogs treated with caiidicidin at the highest dose level. However, discontinuation of the treatment at this dosage level was not necessary. The largest group of dogs (22 animals, 11 female and 11 male) was given candicidin at a sintgle dose level of 5 mg/kg, a dosage level which was comparatively well tolerated. Although the male dogs exhibited a slightly elevated mean cholesterol level prior to