title: Increase of the uterus-relaxant effect of nifedipine by the Abcg2 efflux protein inhibitor KO134 in the rat in vivo.
abstract: OBJECTIVE
  High Abcg2 (ATP-Binding Cassette Transporter Subfamily G, Member-2) levels have been found in reproductive tissues, such as the placenta and uterus. The substrate specificity of Abcg2 is very wide, including uterus-relaxant agents (e.g. nifedipine and prazosine). Through the use of a potent inhibitor (KO134), intracellular accumulation of the substrate can be increased. Nifedipine, commonly used in acute tocolytic therapy, exerts a greater tocolytic effect and has fewer side-effects than β2-adrenergic receptor agonists. The aims of the present study were to investigate the expression of Abcg2 in the rat uterus during gestation and the uterus-relaxant effect of nifedipine in the presence of the Abcg2 inhibitor KO134.
  
  
  METHODS
  Real-time Polymerase Chain Reaction (PCR) and western blot analyses were performed to detect the levels of Abcg2 during gestation in the rat. The uterus-relaxant effect of nifedipine in vivo was investigated by the intra-uterine pressure measuring method, described by Csapo.
  
  
  RESULTS
  Low levels of Abcg2 were found in non-pregnant animals and early-pregnancy (days 6, 8 and 10), but on day 15 of gestation, a sharp increase in Abcg2 levels was observed, which reached its maximum on day 18 and later decreased until the end of gestation. The post-partum levels were similar to those in non-pregnant rats. The in vivo contractility studies revealed that nifedipine had a strong uterus-relaxant effect on spontaneous contractions, and that this effect was significantly and dose-dependently increased by the Abcg2 blocker KO134.
  
  
  CONCLUSIONS
  The administration of efflux pump inhibitors in combination with tocolytic agents may be of novel therapeutic relevance in the management of pre-term labour.
authors.affiliation: Department of Pharmacodynamics and Biopharmacy, Faculty of Pharmacy, University of Szeged, Szeged, Hungary.
authors.forename: Norbert
authors.initials: N
authors.lastname: Lovasz
authors.forename: Eszter
authors.initials: E
authors.lastname: Ducza
authors.forename: Istvan
authors.initials: I
authors.lastname: Zupko
authors.forename: George
authors.initials: G
authors.lastname: Falkay
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000241:Adenosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D054659:Diketopiperazines; D004357:Drug Synergism; D005260:Female; D006576:Heterocyclic Compounds, 4 or More Rings; D008297:Male; D009543:Nifedipine / Q000008:administration & dosage / Q000494:pharmacology*; D011247:Pregnancy; D051381:Rats; D015149:Tocolytic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D014590:Uterine Contraction / Q000187:drug effects / Q000502:physiology; D014599:Uterus / Q000187:drug effects* / Q000502:physiology
chemical_list: C541506:3-(6-isobutyl-9-methoxy-1,4-dioxo-1,2,3,4,6,7,12,12a-octahydropyrazino(1',2'-1,6)pyrido(3,4-b)indol-3-yl)propionic acid tert-butyl ester; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C489249:Abcg2 protein, rat; D054659:Diketopiperazines; D006576:Heterocyclic Compounds, 4 or More Rings; D015149:Tocolytic Agents; D009543:Nifedipine; D000241:Adenosine