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The Effect of Piperine Pro-Nano Lipospheres on Direct Intestinal Phase II Metabolism: The Raloxifene Paradigm of Enhanced Oral Bioavailability
- Source :
- Molecular pharmaceutics. 15(4)
- Publication Year :
- 2018
-
Abstract
- Phase II biotransformation reactions have been gaining more attention due to their acknowledged significance in drug bioavailability, drug development, and drug-drug interactions. However, the predominant role of phase I metabolism has always overshadowed phase II metabolism, resulting in insufficient data regarding its mechanisms. In this paper, we investigate the effect of an advanced lipid based formulation on the phase II metabolism process of glucuronidation, occuring in the enterocytes monolayer. The investigated formulation is a self-emulsifying drug delivery system, termed pro-nano lipospheres, which contains the natural absorption enhancer piperine. To evaluate the effect of this formulation on direct glucuronidation we chose the model molecule raloxifene. First, glucuronidation is the main clearance pathway of this compound without involvement of preceding mechanisms. Second, raloxifene's extensive glucuronidation site is primarily at the intestine. Raloxifene's oral bioavailability was determined in a series of pharmacokinetic experiments using the freely moving rat model. In order to test the effect of the formulation on the relevant UGT enzymes reported in the clinic, we used the in vitro method of UGT-Glo Assay. Coadministration of raloxifene and piperine pro-nano lipospheres to rats resulted in a 2-fold increase in the relative oral bioavailability of raloxifene. However, coadministration of raloxifene with blank pro-nano lipospheres had no effect on its oral bioavailability. In contrast to the difference found in vivo between the two vehicles, both formulations extended an inhibitory effect on UGT enzymes in vitro. Ultimately, these findings prove the ability of the formulation to diminish intestinal direct phase II metabolism which serves as an absorption obstacle for many of today's marketed drugs. Pro-nano lipospheres is a formulation that serves as a platform for the simultaneous delivery of the absorption enhancer and a required drug. The discrepancy found between the in vivo and in vitro models demonstrates that the in vitro method may not be sensitive enough to distinguish the difference between the formulations.
- Subjects :
- Male
Polyunsaturated Alkamides
Chemistry, Pharmaceutical
Glucuronidation
Pharmaceutical Science
Administration, Oral
Biological Availability
Pharmacology
030226 pharmacology & pharmacy
Excipients
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Alkaloids
Drug Delivery Systems
Piperidines
Drug Discovery
medicine
Animals
Raloxifene
Benzodioxoles
Rats, Wistar
Metabolism
Lipids
Metabolic Detoxication, Phase II
Bioavailability
Rats
Intestines
chemistry
Drug development
030220 oncology & carcinogenesis
Piperine
Raloxifene Hydrochloride
Drug delivery
Molecular Medicine
Nanoparticles
Emulsions
Drug metabolism
medicine.drug
Subjects
Details
- ISSN :
- 15438392
- Volume :
- 15
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- Molecular pharmaceutics
- Accession number :
- edsair.doi.dedup.....5f31d74b85631cb83cd6c8ae4d739ed5