Comparative InVitro andInVivoEvaluation ofN-D-Ornithyl Amphotericin B MethylEster, Amphotericin B MethylEster, and Amphotericin B

N-D-Ornithyl amphotericin B methyl ester (0-AME), a semisynthetic derivative ofamphotericin B methyl ester (AME),was compared withamphotericin B(AMB)andAME.Invitro, O-AMEwas more active thanthe othertwoagainst Candida spp.andother fungi andwas onlyslightly affected byinoculum size, addition of serum,orchanges inpH.Invivo, thedoseofO-AMErequired toproduce a 10,000-fold reduction ofCandida albicans ina mouse kidney infection was similar tothatofAMB and1/10thatofAME. Afterintravenous treatment ofinfected miceandratsandsubcutaneous treatment ofmice, average 50% protective dosesfor O-AMEandAMB were similar. Acuteintravenous 50% lethal dosesinmiceindicated thatO-AME was one-ninth astoxic asAMB buttwice astoxic asAME.Acuterenal function tests inratsindicated thatSch28191 was less than1/10 astoxic asAMB andslightly more toxic thanAME.Onthis basis, thecalculated advantage relative toAMB (with AMB equal to1)was 8forO-AMEand1.5forAME. Amphotericin B(AMB)continues tobeoneofthedrugs of choice forthetreatment ofsystemic mycoses inhumans, despite itspoor watersolubility andmany serious side effects. Mechlinski andSchaffner (14)prepared a water- soluble derivative ofAMB, amphotericin B methyl ester (AME)hydrochloride. Thiswas reported tobelesstoxic, butalsolesspotent, thantheparentcompoundinexperi- mental animals (1,8,11). Inan attempt tofind a water-soluble derivative ofAMB withlowertoxicity butequalefficacy toAMB,themethyl esterofN-D-ornithyl amphotericin B (0-AME)was synthe- sized byWright etal.(18). Thepresent article describes the results ofstudies comparing theinvitro andinvivoefficacy ofO-AME,AMB,andAME against Candida albicans and some oftheinvivotoxicities ofthesecompounds.