title: Interaction of triazolam and ketoconazole in P-glycoprotein-deficient mice.
abstract: The role of P-glycoprotein (P-gp) on the distribution of the benzodiazepine triazolam (TRZ) and the azole antifungal agent ketoconazole (KET), and on the TRZ-KET interaction, was studied using mdr1a(-) or mdr1a/b(-/-) mice (P-gp-deficient mice) and matched controls. TRZ and KET also were studied in Caco-2 cells in Transwell culture. After single i.p. injections of TRZ or KET in separate groups of control mice, brain concentrations of TRZ exceeded those in serum [brain/serum area under the concentration curve (AUC) ratio, 5.0], whereas brain/serum AUC ratios for KET were approximately 0.5. On the basis of single time points, brain concentrations of TRZ, or brain/serum ratios, were similar in P-gp-deficient animals compared with controls, whereas P-gp-deficient animals had significantly higher KET brain concentrations and brain/serum ratios. Coadministration of KET with TRZ increased TRZ concentrations in serum, liver, and brain, both in controls and in P-gp-deficient animals, probably attributable to impairment by KET of CYP3A-mediated clearance of TRZ. However, KET did not increase brain/serum ratios of TRZ in either group. In Caco-2 cells, basal-to-apical flux of TRZ was higher than apical-to-basal flux. However, verapamil (100 microM) did not alter flux in either direction. KET inhibited basal-to-apical transport of rho-damine-123, with a 50% inhibitory concentration of 2.7 microM. Thus, TRZ does not appear to undergo measurable blood-brain barrier efflux transport by P-gp in this animal model. KET impairs clearance of TRZ but does not increase tissue uptake. However, KET itself may be a substrate for efflux transport at the blood-brain barrier.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA. lisa.vonmoltke@tufts.edu
authors.forename: Lisa L
authors.initials: LL
authors.lastname: von Moltke
authors.forename: Brian W
authors.initials: BW
authors.lastname: Granda
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Grassi
authors.forename: Michael D
authors.initials: MD
authors.lastname: Perloff
authors.forename: Daesety
authors.initials: D
authors.lastname: Vishnuvardhan
authors.forename: David J
authors.initials: DJ
authors.lastname: Greenblatt
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000172:deficiency* / Q000235:genetics*; D000818:Animals; D018938:Caco-2 Cells; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006801:Humans; D007654:Ketoconazole / Q000493:pharmacokinetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D014229:Triazolam / Q000493:pharmacokinetics*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D014229:Triazolam; D007654:Ketoconazole