title: Placental transfer of quetiapine in relation to P-glycoprotein activity.
abstract: Atypical antipsychotic drugs are well tolerated and thus often preferred in women of fertile age; yet the information on their placental transfer and use during the prenatal period is limited. The aim of this study was to study the placental transfer of quetiapine, a widely used atypical antipsychotic, with special reference to the role of the placental transporter protein, P-glycoprotein (P-gp). This was performed in 18 dually perfused placentas, using the well established P-gp inhibitors PSC833 (valspodar) and GG918 to inhibit the function of P-gp. We also aimed to clarify the significance of two potentially functional ABCB1 single nuclear polymorphisms (SNPs), 2677G>T/A and 3435C>T, on the transplacental transfer (TPT) of quetiapine. The placental transfer of quetiapine in the control group as measured by TPT(AUC) % (absolute fraction of the dose crossing placenta) was 3.7%, which is 29% less than the transfer of the freely diffusible antipyrine, which was 5.2%. The P-gp inhibitors had no significant effect on the transfer of quetiapine as measured by TPT(AUC) % (P = 0.77). No correlation was found between the transplacental transfer of quetiapine (TPT(AUC) %) and placental P-gp expression (P = 0.61). The 3435T allele in exon 26 was associated with significantly higher placental transfer of quetiapine (P = 0.04). We conclude that quetiapine passes the human placenta but that the blood-placental barrier partially limits the transplacental transfer of quetiapine. Administration of P-gp inhibiting drugs with quetiapine is not likely to increase fetal exposure to quetiapine, although the ABCB1 C3435T polymorphism may contribute to inter-individual variation in fetal exposure to quetiapine.
authors.affiliation: Department of Pharmacology and Clinical Pharmacology, Joint Clinical Biochemistry Laboratory of University of Turku, Turku University Central Hospital, Turku, Finland. melissa.rahi@tyks.fi
authors.forename: Melissa
authors.initials: M
authors.lastname: Rahi
authors.forename: Tuija
authors.initials: T
authors.lastname: Heikkinen
authors.forename: Sebastian
authors.initials: S
authors.lastname: Härtter
authors.forename: Jukka
authors.initials: J
authors.lastname: Hakkola
authors.forename: Kristo
authors.initials: K
authors.lastname: Hakala
authors.forename: Ola
authors.initials: O
authors.lastname: Wallerman
authors.forename: Mia
authors.initials: M
authors.lastname: Wadelius
authors.forename: Claes
authors.initials: C
authors.lastname: Wadelius
authors.forename: Kari
authors.initials: K
authors.lastname: Laine
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000166:Acridines / Q000494:pharmacology; D000483:Alleles; D014150:Antipsychotic Agents / Q000493:pharmacokinetics*; D000983:Antipyrine / Q000493:pharmacokinetics; D003524:Cyclosporins / Q000494:pharmacology; D003987:Dibenzothiazepines / Q000493:pharmacokinetics*; D004347:Drug Interactions; D005091:Exons; D005260:Female; D015870:Gene Expression; D005838:Genotype; D006801:Humans; D015151:Immunoblotting; D066298:In Vitro Techniques; D008431:Maternal-Fetal Exchange; D010477:Perfusion; D010920:Placenta / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011247:Pregnancy; D000069348:Quetiapine Fumarate; D044005:Tetrahydroisoquinolines / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000166:Acridines; D014150:Antipsychotic Agents; D003524:Cyclosporins; D003987:Dibenzothiazepines; D044005:Tetrahydroisoquinolines; D000069348:Quetiapine Fumarate; C083501:Elacridar; C070272:valspodar; D000983:Antipyrine