Peri- and Postnatal Developmental Toxicity of Salcaprozate Sodium (SNAC) in Sprague-Dawley Rats

Abstract

Salcaprozate sodium (SNAC) (sodium 8-((2-hydroxybenzoyl) amino) octanoate, CAS RN 203787-91-1) is classified as an oral absorption promoter and may be a useful means for improving the absorption of certain nutrients and pharmaceutical agents. Presented herein is a subset of data from a larger study evaluating the potential effects of SNAC on the gestation, parturition, lactation, maternal behavior, and offspring development of rats. Pregnant Crl:CD BR VAF/Plus female rats (F(0); n = 25) received SNAC at 1000 mg/kg/d orally (gavage) from implantation through lactation and weaning. F(1) pups were exposed in utero and potentially through maternal milk; observations continued through sexual maturity. The study concluded with Caesarean sectioning of F(1) dams for litter observations and fetal evaluations. No deaths, abortions, premature deliveries, or gross lesions occurred in (F(0)) dams. Excess salivation, red perivaginal substance, and slight reductions in body weights, body weight gains, and/or feed intake were noted in late gestation/early lactation. SNAC was associated with a prolonged gestation period, leading to a greater number of dams with stillborn pups, higher number of stillborn pups, and reduced live litter size. Offspring body weights/gains, feed consumption, age of sexual maturation, mating, fertility, behavioral parameters, and organ weights at necropsy were unaffected by SNAC. No gross external changes were observed in F(1) or F(2) pups. In summary, SNAC administered orally at 1000 mg/kg/d to pregnant rats from gestation to weaning resulted in a slight decrease in maternal body weights (-3.8%) and prolonged gestation, along with an increase in stillbirths, but had no effects on growth and development in surviving offspring.

Intestinal Permeation Enhancers for Oral Delivery of Macromolecules: A Comparison between Salcaprozate Sodium (SNAC) and Sodium Caprate (C10)

“…For SNAC, Riley et al carried out a sub-chronic oral toxicity test of SNAC in rats and found a no observed adverse effect (NOAEL) level of 1 g/kg/day in rats for up to 13 weeks; it was only a massive dose of 2 g/kg/day that eventually caused significant mortality [78]. It was also examined for gestational toxicity in pregnant rats at oral doses up to 1 g/kg/day where slight weight loss was seen; there was no effect on growth of pups, but some evidence of a small increase in the still-birth rate was noted [79]. Some GI effects including emesis and diarrhea were observed in studies involving monkeys at a dose of ≥1.8 g/kg/day [80].…”

Gastrointestinal Permeation Enhancers for the Development of Oral Peptide Pharmaceuticals

“…In the peri-and post-natal developmental toxicity study, oral administration of 1 g/kg/day from implantation to lactation of rats was conducted to evaluate the exposure and toxicity of SNAC in the uterus and breast milk of the offspring. There was no effect on the growth and development of surviving offspring exposed to SNAC, albeit that an increase in the number of stillbirths during pregnancy was observed [146]. Unlike MCFA, given that it does not exist in nature, SNAC may have more safety considerations.…”

Toward Effective Long-Term Prevention of Thromboembolism: Novel Oral Anticoagulant Delivery Systems

“…47 Recently, SNAC has achieved a ''generally regarded as safe'' (GRAS) status concurrently with published data on its toxicity. 48,49 The second clinically tested approach to increase heparin oral bioavailability also relies on coadministration with drug delivery agents, namely permeation enhancers. LMWH has been successfully combined with medium chain fatty acids in gastro-resistant tablets and yielded 8% oral bioavailability of LMWH in phase 1 clinical trial.…”