| 1. |
- Jönsson, Karin, et al.
(författare)
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Evaluation of the degradation of desamino1,D-arginine8-vasopressin by nasal mucosa.
- 1992
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Ingår i: Acta Endocrinologica. - : Oxford University Press (OUP). - 0001-5598 .- 0804-4643 .- 1479-683X. ; 127:1, s. 27-32
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Tidskriftsartikel (refereegranskat)abstract
- The nasal route is a convenient and simple way to administer peptides to humans. Absorption of the drug, however, requires passage of the substance through the nasal mucosa. This is a possible site of enzymatic degradation of the peptide. It is shown that rabbit nasal mucosa homogenates rapidly degrade the synthetic anti-diuretic hormone analogue desamino1,D-arginine8-vasopressin in vitro. The metabolite formed has been identified as des-(amino,arginine8,glycineamide9)-vasopressin, which is stable under the prevalent in vitro incubation conditions. It is proposed that this process is catalyzed by intracellular post-proline cleavage enzyme. Reversed phase chromatography in combination with immunological detection has been used to study the possible presence of this metabolite in the circulation after intranasal administration to humans. The metabolite des-(amino,arginine8,glycineamide9)-vasopressin could not be detected in plasma following intranasal administration, possibly indicating a paracellular absorption of desamino1,D-arginine8-vasopressin or absence of this enzymatic activity in humans.
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| 2. |
- Lundin, Stefan, et al.
(författare)
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Differences in transport rate of oxytocin and vasopressin analogues across proximal and distal isolated segments of the small intestine of the rat.
- 1991
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Ingår i: Pharmaceutical Research. - 1573-904X. ; 8, s. 1274-1280
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Tidskriftsartikel (refereegranskat)abstract
- The transmural intestinal passage of some oxytocin and vasopressin analogues (oxytocin, OT; [Mpa1, D-Arg8]vasopressin, dDAVP; [Mpa1, Tyr (OMe)2, carba6]oxytocin, carbetocin; [Mpa1, D-Tyr (OEt)2, Thr4, Orn8]vasotocin, antocin II; [Mpa1, D-Tyr (OEt)2, Thr4, desPro7Orn8Gly9NH2]tocinoic acid-NH(CH2)3NH2, desPOG-antocin II-NH(CH2)3NH2) was studied using isolated proximal and distal segments in the rat. All peptides (measured as peptide-like immunoreactivity) displayed a higher transport rate across distal intestinal segments as determined by radioimmunoassay (RIA). The smallest peptide, des POG-antocin II-NH(CH2)3NH2, was transported at the fastest rate. No correlation of lipophilicity with transport rate was observed. Determination of the amount of peptide remaining in the mucosal media at the end of the incubation period by HPLC did not reveal any visible degradation products. However, the large difference in transport rate between [3H]OT and immuno-reactive OT indicates mucosal metabolism of this peptide. [3H]d-DAVP was distributed in a larger mucosal volume than the extracellular space marker [3H]inulin, indicating tissue uptake, but was too low (
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| 3. |
- Lundin, Stefan, et al.
(författare)
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Pharmacokinetic and pharmacologic properties of antiuterotonic oxytocin analogs in the rat
- 1993
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Ingår i: Journal of Pharmacology and Experimental Therapeutics. - 1521-0103. ; 264:2, s. 783-788
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Tidskriftsartikel (refereegranskat)abstract
- The pharmacologic and pharmacokinetic properties were evaluated in a series of antiuterotonic oxytocin analogs, modified at positions 1, 2, 4, 8 and, in one case, position 9 of the oxytocin (OT) molecule. [Mpa1,D-Tyr2(Et),Val4,Orn8,desGly9]-OT, [Mpa1,Tyr2(Et),Val4,Orn8]-OT and [Mpa1,D-Tyr2,Val4,Orn8]-OT displayed similar plasma clearance rates (Clps) using the constant infusion method in rats. Two analogs, [Mpa1,D-Tyr2(Et),Val4,Orn8]-OT and, particularly, [Mpa1,D-Tyr2(Et),Thr4,Orn8]-OT, were cleared at significantly higher rates compared with the others. [Mpa1, D-Tyr2(Et), Val4, Orn8]-OT and [Mpa1, D-Tyr2(Et), Thr4, Orn8, desGly9]-OT were most potent in eliciting a short-term in vivo antiuterotonic effect, whereas the duration of effect was longest for [Mpa1, D-Tyr2, Val4, Orn8]-OT and [Mpa1, D-Tyr2(Et), Thr4, Orn8, desGly9]-OT. The Clp of [Mpa1, D-Tyr2, Val4, Orn8]-OT was similar regardless of the infusion rate. No relationship between antiuterotonic effect and Clp of the five peptides could be demonstrated, and no significant linear correlation between Clp and effect duration was found. The apparent volumes of distribution for the present analogs were 10-fold larger than the blood volume, a finding to be considered when measuring in vivo antagonistic activity. The 24-h urinary excretion ranged from 14.3 to 25.6% of the i.v. dose and was negatively correlated with peptide lipophilicity. It is concluded that, in addition to diverging pharmacologic properties, peptide analogs may differ markedly in kinetic parameters like Clp, volumes of distribution and urinary excretion despite minor molecular modifications.
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