GASTROINTESTINAL ABSORPTION AND PLASMA-CLEARANCE RATES OF [D-ARG(8)]VASOPRESSIN ANALOGS IN THE RAT

The gastrointestinal absorption of a series of vasopressin (VP) analog ues with enhanced enzymatic stability was determined in chronically ca theterized, conscious rats. The following peptides were used: [Mpa(1), D-Arg(8)]vasopressin (dDAVP), [Mpa(1),Asn(4),D-Arg(8)] VP, [Mpa(1),Val (4),D-Arg(8)]VP, [Mpa(1),(CH3)(3)Ala(4),D-Arg(8)] VP, [Mpa(1),Tyr(ethy l)(2),D-Arg(8)] VP, and [Mpa(1),D-Tyr(ethyl)(2),Ile(3),Val(4),D-Arg(8) ]VP. The peptides were administered by gavage feeding and blood sample s were taken repeatedly for 3 h. In another series of experiments, pla sma clearance rates (Cl-p) were determined using the constant infusion method. Plasma concentrations were measured by use of a cross-reactin g dDAVP antiserum in a radioimmunoassay method. The bioavailability of all peptides was below 0.1%. The Cl-p values differed sevenfold; the lowest was for [Mpa(1),D-Tyr(ethyl)(2),Ile(3),Val(4),D-Arg(8)]VP and t he highest was for [Mpa(1),Asn(4),D-Arg(8)]VP. With the exception of d DAVP the Cl-p values of the analogues showed an inverse relationship w ith hydrophilicity. Incubations in relatively concentrated intestinal contents for 1 h showed extensive degradation of the analogues except for [Mpa(1),D-Tyr(ethyl)(2),Ile(3),Val(4),D-Arg(8)]VP. It can be concl uded that, in the rat, the bioavailability of dDAVP is lower than in o ther animal species and in man. Increased resistance to peptide degrad ation by gastrointestinal contents did not improve absorption. Therefo re, the permeability properties of the intestinal mucosa are likely to be a more important factor affecting the gastrointestinal absorption of this group of peptides, although postabsorption events, like hepati c extraction, may also play a role.