Information regarding the metabolic fate of the neurohypophyseal hormones arginine-vasopressin (AVP), oxytocin (OT) and their analogues in man is practically non-existent. The aim of the present study was to investigate the stability of oxytocin, vasopressin and their analogues dDAVP and [Mpa1-D-Tyr2(Et), Thr4, Orn8]-oxytocin (antocin) in human renal microvilli brush border membranes and in human liver membranes. After incubation the extent of degradation of the peptides was determined by reversed phase high-performance liquid chromatography (HPLC). The degradation of both AVP and OT was rapid in the presence of glutathione and human renal microvilli membranes. AVP, as well as dDAVP, was stable when incubated with microvilli membranes without glutathione, while OT was metabolized. The metabolization of the oxytocin analogue, antocin, also varied with the presence of glutathione. While in the absence of glutathione a more lipophilic peak eluted, a more hydrophilic peak was observed with glutathione on HPLC. The lipophilic peak was found to coelute with the truncated analogue [Mpa1, D-Tyr2 (Et), Thr4, desOrn8, Gly9]-oxytocin. No degradation occurred when the peptides were incubated with liver membranes. However, when using crude, unpurified liver homogenate degradation occurred for all peptides except antocin. The degradation of AVP in the human unpurified liver homogenate was as rapid as in the renal microvilli membranes. Similarly, OT was more rapidly degraded in human kidney microvilli membranes in the presence of glutathione than in the human crude liver homogenate, when using equal amounts of protein in the incubations. Thus, the present investigation indicates the existence of two possible metabolic pathways, in kidney microvilli, one for OT, which did not require the presence of reduced glutathione, and one for AVP, which required the presence of reduced glutathione. Liver degradation, on the other hand, requires the hepatocytes.