Abstract
The intestinal absorption enhancement of the nonapeptide [Mpa1,d-Arg8]vasopressin (dDAVP) by medium-chain glyceride vehicles was studied using anin vivo rat model. Rats were gavaged with dDAVP formulated with three different lipid vehicles: (1) monohexanoin, (2) mixed monoglycerides, diglycerides and triglycerides of hexanoic acid and (3) monoglycerides, diglycerides and triglycerides of octanoic and decanoic acids, and with saline as control. The marker absorption into blood and urine was followed for 24 hr. All lipid vehicles enhanced the oral bioavailability of dDAVP, but monohexanoin gave the highest increase, ∼10 times that of control. In contrast to dDAVP, the stable and more lipophilic nonapeptide analog [Mpa1,d-Tyr(ethyl)2,Val4,d-Arg8]oxytocin did not show increased urine recovery when formulated with monohexanoin. A 2-fold increase in urine recovery of the inert low-molecular-weight marker [51Cr]EDTA was observed when formulated with monohexanoin. With use of the fluorescent marker Evans blue formulated with monohexanoin, an elevated accumulation of Evans blue in the mucus layer was observed after incubation in in situ loops. No mucosal damage after lipid vehicle gavage was observed by light microscopic evaluation. Medium-chain glycerides functioned well as oral absorption enhancers of the model peptide dDAVP, and monohexanoin showed the highest enhancement capacity. The mechanisms of this enhancement appear to be related to a protection against luminal dDAVP degradation, mucoadhesive properties of the vehicle and, possibly, an altered epithelial absorption pathway.
Footnotes
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Send reprint requests to: Dr. Pål Lundin, Department of Animal Physiology, Lund University, Helgonavägen 3B, S-223 62 Lund, Sweden. E-mail:Pal.Lundin{at}zoofys.lu.se
- Abbreviations:
- CAT
- [Mpa1,d-Tyr(Ethyl)2,Val4,d-Arg8]oxytocin
- C6
- monohexanoin
- C6 M
- mixed glycerides of hexanoic acid
- C8/10 M
- mixed glycerides of octanoic and decanoic acids
- dDAVP (desmopressin)
- [Mpa1,d-Arg8]vasopressin
- NAC
- N-acetyl-l-cysteine
- AUC
- area under the plasma marker concentration-time curve
- Received November 11, 1996.
- Accepted April 2, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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