title: Effect of the novel anxiolytic drug deramciclane on the pharmacokinetics and pharmacodynamics of the CYP3A4 probe drug buspirone.
abstract: BACKGROUND
  Preliminary in vitro findings indicated that the novel anxiolytic drug, deramciclane is a substrate for the cytochrome P(450) (CYP) 3A4 isoenzyme. Moreover, its co-administration with buspirone, another anxiolytic drug, is likely in clinical practice.
  
  
  OBJECTIVE
  The primary objective of the present study was to evaluate the in vivo effects of deramciclane on CYP3A4 activity as measured by buspirone pharmacokinetics. The secondary objective was to study the possible pharmacodynamic interaction between these two anxiolytic drugs.
  
  
  METHODS
  Sixteen healthy subjects received 60 mg deramciclane or matched placebo for 8 days in this randomized, double-blind, cross-over study. On day 8 of both phases, the subjects received a 20-mg single dose of buspirone. Buspirone and its active metabolite, 1-pyrimidylpiperazine (1-PP), concentrations were measured for 24 h. Pharmacodynamic testing and measurement of plasma prolactin concentrations were carried out on day 7 and day 8 to assess the pharmacodynamic consequences of deramciclane and buspirone co-administration.
  
  
  RESULTS
  Repeated administration of deramciclane had no effect on CYP3A4 activity as measured by buspirone pharmacokinetics. However, deramciclane administration caused an inhibition of the further, not CYP3A4-dependent, metabolism of 1-PP as evidenced by 84% increase in the AUC ( P<0.001) and 20% increase in the elimination half-life ( P=0.0012) of 1-PP. Deramciclane did not potentiate the buspirone-induced increase in prolactin secretion. No significant differences were found in the psychomotoric testing or the subjective maximum sedation between the deramciclane phase and the placebo phase, either before or after buspirone administration. Of 16 subjects, 5 experienced dizziness during both study phases.
  
  
  CONCLUSIONS
  Deramciclane does not inhibit CYP3A4 activity as measured by buspirone pharmacokinetics, and there were no indications of relevant pharmacodynamic interaction after multiple doses of deramciclane and a single dose of buspirone.
authors.affiliation: Department of Pharmacology and Clinical Pharmacology, University of Turku, It. Pitkäkatu 4B, FIN-20520, Turku, Finland. karlai@utu.fi
authors.forename: Kari
authors.initials: K
authors.lastname: Laine
authors.forename: Outi
authors.initials: O
authors.lastname: Ahokoski
authors.forename: Risto
authors.initials: R
authors.lastname: Huupponen
authors.forename: Jutta
authors.initials: J
authors.lastname: Hänninen
authors.forename: Sanna
authors.initials: S
authors.lastname: Palovaara
authors.forename: Jori
authors.initials: J
authors.lastname: Ruuskanen
authors.forename: Harry
authors.initials: H
authors.lastname: Björklund
authors.forename: Markku
authors.initials: M
authors.lastname: Anttila
authors.forename: Juha
authors.initials: J
authors.lastname: Rouru
mesh_terms: D000284:Administration, Oral; D000328:Adult; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D019540:Area Under Curve; D002065:Buspirone / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D001892:Camphanes / Q000494:pharmacology*; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004311:Double-Blind Method; D004347:Drug Interactions; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D013997:Time Factors
chemical_list: D014151:Anti-Anxiety Agents; D001892:Camphanes; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C037921:1-(2-pyrimidinyl)piperazine; C060555:deramciclane; D002065:Buspirone