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ties affecting vaginal absorption. it is generally accepted that low molecular weight
lipophilic substances are likely to be absorbed more than large molecular weight lipophilic
or hydrophilic drugs. Generally, hydrophilic compounds prefer the paracellular
route, with its molecular size being inversely related to its absorption rate.
Whereas, lipophilic compounds prefer the transcellular route, most commonly by
passive diffusion through the epithelium down the concentration gradient. The intravaginal
devices impregnated with progesterone or synthetic progestagen such as
fluorogestone acetate (FGa) or medroxyprogesterone acetate (maP) are usually employed
in other species (Karaca et al., 1999). These steroids are lipophilic, have low
molecular weight and are absorbed continuously through the mucose during a period
of time.
however, since vaginal fluids have some amount of water, any substance intended
for vaginal delivery requires a certain degree of solubility on water (hussain and ahsan,
2005). Gonadotropin-releasing hormone (Gnrh) is a hypothalamic decapeptide
that plays a critical role in the regulation of reproductive processes (Conn and
Crowley, 1994). Gnrh is a member of a larger family of peptides that is present in
every vertebrate class examined thus far (Tsai and Zhang, 2008). Currently, 23 different
isoforms of Gnrh have been identified in various species (metallinou et al.,
2007). all of these peptides consist of 10 amino acids having a similar structure, with
at least 50% sequence homology (dubois et al., 2002). They have been named according
to the species from which they were originally isolated (metallinou et al.,
2007). Gnrh analogues, triptorelin, leuprolide, buserelin, gonadorelin, dalmarelin,
etc. are used to induce ovulation in rabbit does by means an i.m. injection. recently,
some studies have demonstrated that ovulation can be induced in rabbit females by
absorption through the vaginal mucosa of different Gnrh analogues included in the
seminal dose, avoiding i.m. administration (Viudes de Castro et al., 2007; ondruska
et al., 2008; Quintela et al., 2008). Vicente et al. (2008) suggest that there are some
factors influencing absorption of Gnrh by the vaginal mucosa: the state of mucosa
(secretions induce by receptivity state of female), extender composition and probably
the capacity of sperm to incorporate foreign molecules.
moreover, Gnrh analogues are susceptible to the proteolytic enzymes due to its peptidic
characteristic resulting in low intestinal absorption and bioavailability (less that
1%) following either oral or intraduodenal injections in several animal models. The
Gnrh analogues can be hydrolyzed at three bonds Trp 3 -ser 4 , ser 4 -Tyr 5 , Tyr 5 -Gly 6 , the
first one being the preferred (stephenson and Kenny 1988). The cell layers of the vagina
retain most of the enzyme activity. among the enzymes present, proteases are
likely to be the prominent barrier for the absorption of intact peptide and protein into
the systemic circulation. in rabbit vaginal epithelium extracts there are high concentrations
of aminopeptidases (sayani et al., 1993). maybe it is one of the reason by it
is necessary increasing about 10 times the i.m. dose of buserelin, when it is included
in the intravaginal seminal doses.
in summary, some studies have demonstrated that ovulation can be induced in rabbit
females by absorption through the vaginal mucosa of different Gnrh analogues
included in the seminal dose, avoiding i.m. administration. a long list of factors affects
the efficacy of above intravaginal administration: the dissolution degree in vag-
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