title: Pharmacokinetic interaction study between flavanones (hesperetin, naringenin) and rasagiline mesylate in wistar rats.
abstract: Cytochrome P-450 (CYP) enzymes and P-glycoprotein (P-gp) play an important role in the oral bioavailability and first-pass-metabolism (FPM) of many drugs. Rasagiline is a selective, monoamine oxidase-B inhibitor and it undergoes significant FPM in the liver prior to excretion by CYP1A2. Hesperetin and naringenin are naturally occurring flavanones and are reported as modulators of CYP enzymes and P-gp. The objective of the present investigation was to evaluate the effect of hesperetin and naringenin on the pharmacokinetics (PK) of rasagiline in rats. Rats were treated orally with rasagiline (2 mg/kg) alone and co-administered with hesperetin and naringenin (12.5 and 25 mg/kg) for 15 consecutive days. Blood samples were collected from tail vein on the 1st day in a single dose PK study (SDS) and on 15th day in the multiple dose PK study (MDS). Hesperetin and naringenin co-administration significantly enhanced the area under the curve (AUC), maximum plasma concentration (Cmax) and elimination half life (t1/2) of rasagiline with a concomitant reduction in clearance (CL/F) in both SDS and MDS. Rasagiline concentrations were significantly increased when co-administered with hesperetin and naringenin in the brain. No significant difference was found in rasagiline transport from mucosal to serosal side in the presence of hesperetin and naringenin ex vivo (rat everted gut sacs used). Our findings suggested that hesperetin and naringenin enhanced the systemic exposure of rasagiline might be through the inhibition of CYP1A2 but not P-gp. Further studies are needed on CYP1A2 and P-gp over expressed cells to confirm this interaction at cellular level.
authors.affiliation: a Drug Metabolism and Pharmacokinetics Division , KVSR Siddhartha College of Pharmaceutical Sciences , Vijayawada , Andhra Pradesh , India.
authors.forename: Ravindrababu
authors.initials: R
authors.lastname: Pingili
authors.affiliation: a Drug Metabolism and Pharmacokinetics Division , KVSR Siddhartha College of Pharmaceutical Sciences , Vijayawada , Andhra Pradesh , India.
authors.forename: Sridhar
authors.initials: S
authors.lastname: Vemulapalli
authors.affiliation: a Drug Metabolism and Pharmacokinetics Division , KVSR Siddhartha College of Pharmaceutical Sciences , Vijayawada , Andhra Pradesh , India.
authors.forename: Surya Sandeep
authors.initials: SS
authors.lastname: Mullapudi
authors.affiliation: a Drug Metabolism and Pharmacokinetics Division , KVSR Siddhartha College of Pharmaceutical Sciences , Vijayawada , Andhra Pradesh , India.
authors.forename: Siddhartha
authors.initials: S
authors.lastname: Nuthakki
authors.affiliation: a Drug Metabolism and Pharmacokinetics Division , KVSR Siddhartha College of Pharmaceutical Sciences , Vijayawada , Andhra Pradesh , India.
authors.forename: Sivaprasad
authors.initials: S
authors.lastname: Pendyala
authors.affiliation: a Drug Metabolism and Pharmacokinetics Division , KVSR Siddhartha College of Pharmaceutical Sciences , Vijayawada , Andhra Pradesh , India.
authors.forename: Naveenbabu
authors.initials: N
authors.lastname: Kilaru
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D004347:Drug Interactions; D044950:Flavanones / Q000008:administration & dosage / Q000494:pharmacology*; D006569:Hesperidin / Q000008:administration & dosage / Q000494:pharmacology*; D007189:Indans / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008996:Monoamine Oxidase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D017208:Rats, Wistar; D013116:Spinal Cord / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D044950:Flavanones; D007189:Indans; D008996:Monoamine Oxidase Inhibitors; C031967:rasagiline; D006569:Hesperidin; C017170:Cyp1a2 protein, rat; D019388:Cytochrome P-450 CYP1A2; C005273:naringenin; C013015:hesperetin
keywords: CYP enzymes; digoxin; first pass metabolism; pharmacokinetics; rat everted gut sacs