title: Effects of HM30181, a P-glycoprotein inhibitor, on the pharmacokinetics and pharmacodynamics of loperamide in healthy volunteers.
abstract: OBJECTIVE
  HM30181 is a third generation P-glycoprotein (P-gp) inhibitor currently under development. The objectives of this study were to evaluate the effects of a single dose of HM30181 on the pharmacodynamics and pharmacokinetics of loperamide, a P-gp substrate, and to compare them with those of quinidine.
  
  
  METHODS
  Eighteen healthy male subjects were administered loperamide alone (period 1) or with loperamide plus quinidine or HM30181 in period 2 or 3, respectively. In period 3, subjects randomly received one of three HM30181 doses: 15, 60 or 180 mg. Changes in pupil size, alertness, oxygen saturation and the oral bioavailability of loperamide were assessed in each period. In addition, the pharmacokinetics of HM30181 were determined.
  
  
  RESULTS
  Pupil size, alertness and oxygen saturation did not change over time when loperamide alone or loperamide plus HM30181 was administered while HM30181 significantly increased the systemic exposure to loperamide, i.e. the geometric mean ratio (90% confidence interval) of AUC(0,tlast ) for loperamide with and without HM30181 was 1.48 (1.08, 2.02). Co-administered quinidine significantly increased the systemic exposure to loperamide 2.2-fold (1.53, 3.18), which also markedly reduced pupil size, resulting in a decrease of 24.7 mm h in the area under the effect curve of pupil size change from baseline compared with loperamide alone.
  
  
  CONCLUSIONS
  HM30181 inhibits P-gp mainly in the intestinal endothelium, which can be beneficial because pan-inhibition of P-gp, particularly in the brain, could lead to detrimental adverse events. Further studies are warranted to investigate adequately the dose-exposure relationship of HM30181, along with its duration of effect.
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea.
authors.forename: Tae-Eun
authors.initials: TE
authors.lastname: Kim
authors.forename: Howard
authors.initials: H
authors.lastname: Lee
authors.forename: Kyoung Soo
authors.initials: KS
authors.lastname: Lim
authors.forename: SeungHwan
authors.initials: S
authors.lastname: Lee
authors.forename: Seo-Hyun
authors.initials: SH
authors.lastname: Yoon
authors.forename: Kyung-Mi
authors.initials: KM
authors.lastname: Park
authors.forename: Hyesun
authors.initials: H
authors.lastname: Han
authors.forename: Sang-Goo
authors.initials: SG
authors.lastname: Shin
authors.forename: In-Jin
authors.initials: IJ
authors.lastname: Jang
authors.forename: Kyung-Sang
authors.initials: KS
authors.lastname: Yu
authors.forename: Joo-Youn
authors.initials: JY
authors.lastname: Cho
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000328:Adult; D000930:Antidiarrheals / Q000493:pharmacokinetics / Q000494:pharmacology; D019540:Area Under Curve; D001578:Benzopyrans / Q000008:administration & dosage / Q000494:pharmacology*; D001682:Biological Availability; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007546:Isoquinolines / Q000008:administration & dosage / Q000494:pharmacology*; D008139:Loperamide / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D011680:Pupil / Q000187:drug effects; D011802:Quinidine / Q000494:pharmacology*; D013777:Tetrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D055815:Young Adult
chemical_list: C521083:4-oxo-4H-chromene-2-carboxylic acid (2-(2-(4-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl)-phenyl)-2H-tetrazol-5-yl)-4,5-dimethoxyphenyl)amide; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000930:Antidiarrheals; D001578:Benzopyrans; D007546:Isoquinolines; D013777:Tetrazoles; D008139:Loperamide; D011802:Quinidine
keywords: HM30181; P-glycoprotein inhibitor; loperamide; pharmacodynamics; pharmacokinetics