Vasopressins pharmacokinetics

The search for an effective non-peptide oxytocin antagonist has become a major goal of a number of pharmaceutical companies because of the poor pharmacokinetic properties and especially the lack of oral bioavailability associated with peptidic antagonists. Early research in this field was dominated by Merck, but in recent years significant research efforts at GlaxoSmithKline and Serono have been published. A number of other companies, notably Sanofi-Aventis, Yamanouchi and Wyeth, have had a major presence in vasopressin receptor research and oxytocin is frequently included in patent claims for the molecules. Occasionally, oxytocin-selective compounds have been reported, usually derived by adaptation of the vasopressin antagonist template. 

Preterm labour is the major cause of perinatal morbidity and mortality. Oxytocin antagonists offer an attractive approach to prevention. Chapter 7 reviews three decades of medicinal chemistry in this field. The peptide approach has resulted in valuable injectable products. Selectivity over the related vasopressin receptors and improvement in pharmacokinetic profile have been the key challenges for more recent non-peptide programmes, and these seem likely to yield orally available medicines. 

PHARMACOKINETICS When vasopressin and desmopressin are given orally, they are rapidly inactivated by trypsin, which cleaves the peptide bond between amino acids 8 and 9. Inactivation by peptidases in various tissues (particularly the Uver and kidneys) results in a plasma tj of vasopressin of 17-35 minutes. Following intramuscular or subcutaneous injection, the antidiuretic effects of vasopressin last 2-8 hours. The plasma t of desmopressin has a fast component of 6.5-9 minutes and a slow component of 30-117 minutes. Only 3% and 0.15%, respectively, of intranasaUy and orally administered desmopressin is absorbed. 

Fjellestad-Panlsen A, Lnndin H P, Panlsen O (1993). Pharmacokinetics of 1-Deamino-8-arginine vasopressin after varions rontes of administration in healthy volunteers. Clin. Endocortinol. 38 177-182. 

However, compounds of the type 89 were reported to have low solubility and relatively high log D. This resulted in replacement of the 3,4-difluorobenzaldehyde with 2-methyloxazole-4-aldehyde in the U-4CR. Compound 92 (GSJC221149A) has been noted to have nanomolar affinity for the oxytocin receptor with > 1400-fold selectivity over the closely related vasopressin receptors. Compound 92 (Figure 7.3) has also shown to have a good rat pharmacokinetic profile and low human microsomal clearance and inhibits oxytocin-induced contraction in vivo in the anesthetized rat... 

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