title: Itraconazole and domperidone: a placebo-controlled drug interaction study.
abstract: OBJECTIVE
  To determine the influence of itraconazole on the pharmacokinetics, and the CNS and prolactin-elevating effects of domperidone in humans.
  
  
  METHODS
  Fifteen healthy volunteers received either itraconazole (200 mg daily) or placebo for 5 days with a double blind, randomized, cross-over design. A single oral 20-mg dose of domperidone was administered to subjects on day 5. Plasma domperidone and serum prolactin concentrations were measured. The effects of domperidone on CNS were also assessed using self-rating scales and electroencephalography.
  
  
  RESULTS
  Itraconazole significantly increased domperidone AUC(0-∞) (3.2-fold) and C(max) (2.7-fold) compared with placebo, but had no significant effect on the elimination half-life of domperidone. The CNS effects of domperidone assessed by self-rating of mood and electroencephalography, and the prolactin-elevating effect, were not significantly affected by itraconazole. A counterclockwise hysteresis was evident in the relationship between plasma domperidone and serum prolactin concentrations. Itraconazole shifted the hysteresis to the right. Concentration-effect modeling procedures yielded a significant linear relationship between hypothetical effect site domperidone concentrations and prolactin levels. Itraconazole reduced the slope of the linear relationship.
  
  
  CONCLUSIONS
  Itraconazole significantly increased plasma domperidone concentrations. The interaction is probably mainly due to a reduced first pass elimination by inhibition of CYP3A and/or MDR1. The clinical significance of the altered relationship between domperidone concentrations and prolactin levels caused by itraconazole is still to be determined.
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Yufu-shi, Oita 879-5593, Japan.
authors.forename: Tsuneaki
authors.initials: T
authors.lastname: Yoshizato
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Kotegawa
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Imai
authors.forename: Kimiko
authors.initials: K
authors.lastname: Tsutsumi
authors.forename: Junko
authors.initials: J
authors.lastname: Imanaga
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Ohyama
authors.forename: Kyoichi
authors.initials: K
authors.lastname: Ohashi
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000284:Administration, Oral; D000328:Adult; D000339:Affect / Q000187:drug effects; D000935:Antifungal Agents / Q000008:administration & dosage*; D019540:Area Under Curve; D001711:Biotransformation; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D004294:Domperidone / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D018492:Dopamine Antagonists / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004347:Drug Interactions; D004569:Electroencephalography; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D006207:Half-Life; D006801:Humans; D017964:Itraconazole / Q000008:administration & dosage*; D007564:Japan; D016014:Linear Models; D008297:Male; D049990:Membrane Transport Modulators / Q000008:administration & dosage; D008657:Metabolic Clearance Rate; D011388:Prolactin / Q000097:blood; D057566:Self Report; D015854:Up-Regulation; D055815:Young Adult
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000935:Antifungal Agents; D065692:Cytochrome P-450 CYP3A Inhibitors; D018492:Dopamine Antagonists; D004791:Enzyme Inhibitors; D049990:Membrane Transport Modulators; D017964:Itraconazole; D004294:Domperidone; D011388:Prolactin; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A