title: Enhancement of oral bioavailability of rivastigmine with quercetin nanoparticles by inhibiting CYP3A4 and esterases.
abstract: BACKGROUND
  Quercetin is a well-known flavonoid, has pharmacokinetic interaction with ester drugs due to its capability of esterase inhibition in the gut and liver. However, the interaction between quercetin nanoparticles (NQC) and rivastigmine has not been reported. Hence, the present study was performed to evaluate the effect of quercetin alone and its nanoparticles on the pharmacokinetics of rivastigmine in rats.
  
  
  METHODS
  NQC prepared by antisolvent precipitation method. The influence of quercetin on the pharmacokinetics of rivastigmine was evaluated by following methods i.e. in vitro inhibitory effect on esterase enzyme in rat liver microsomes and in vitro assessment of CYP3A activity using erythromycin-N-demethylase (EMD) assay. To confirm these findings, an in vivo pharmacokinetic study of orally administered rivastigmine in rats with quercetin and NQC pretreatments was performed.
  
  
  RESULTS
  The size of NQC was observed below 300nm. Quercetin significantly (p<0.05) inhibited the esterase-mediated metabolism of rivastigmine. In in vitro assessment of CYP3A activity model the erythromycin-N-demethylation (EMD) levels in quercetin treated group were significantly reduced (p<0.05). Cmax, AUC0-tand AUC0- ∞of rivastigmine were found to be increased in quercetin and NQC pretreated groups. Further, the CL/F and Vd/F of rivastigmine were significantly decreased.
  
  
  CONCLUSIONS
  The results revealed that enhanced bioavailability of rivastigmine might be caused by the combination of their effects due to CYP3A and esterase inhibition, Therefore, concomitant administration of NQC influences the bioavailability of rivastigmine and also has synergetic effect in the treatment of Alzheimer's disease.
authors.affiliation: DMPK & Clinical Pharmacology, University College of Pharmaceutical Sciences, Kakatiya University, Telangana, Warangal, TS, India.
authors.forename: Suresh
authors.initials: S
authors.lastname: Palle
authors.affiliation: DMPK & Clinical Pharmacology, University College of Pharmaceutical Sciences, Kakatiya University, Telangana, Warangal, TS, India. Electronic address: prasadneerati@gmail.com.
authors.forename: Prasad
authors.initials: P
authors.lastname: Neerati
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000494:pharmacology*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004950:Esterases / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D053758:Nanoparticles / Q000008:administration & dosage*; D011794:Quercetin / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D000068836:Rivastigmine / Q000493:pharmacokinetics*
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D011794:Quercetin; C465260:Cyp3a2 protein, rat; D051544:Cytochrome P-450 CYP3A; D004950:Esterases; D000068836:Rivastigmine
keywords: Nanoparticles; Pharmacokinetics; Quercetin; Rivastigmine