Evaluation of the interaction of loratadine and desloratadine with P-glycoprotein

Drug Metab Dispos. 2001 Aug;29(8):1080-3.

Abstract

The absorption of many drugs is affected by their interaction with ATP-binding cassette (ABC) transporters. The most extensively studied of these ABC transporters is the proein product of MDR1 (multidrug resistance) that encodes a 170-kDa integral plasma membrane phosphorylated glycoprotein known as P-glycoprotein (P-gp). The purpose of this study was to determine, using two different methods, whether the nonsedating antihistamine loratadine (L) and its active metabolite desloratadine (DL) interact with P-gp. MDR cells presenting human P-gp were incubated with the fluorescent P-gp substrate daunorubicin with or without L, DL, and several positive controls. The IC(50) of loratadine (approximately 11 microM) was approximately 160 times the maximum observed plasma concentration (C(max)) following a dose of 10 mg. The IC(50) of desloratadine (approximately 43 microM) was approximately 880 times the C(max) following a dose of 5 mg. The positive control, cyclosporin A, had an IC(50) of approximately 1 microM. ATP hydrolysis activity was measured in the membrane fraction prepared from MDR cells presenting P-gp, which were exposed to various concentrations of test compounds. Known substrates of P-gp demonstrated clear, repeatable, concentration-dependent increases in ATP hydrolysis activity. L caused an increase in ATPase activity above basal levels. L had a V(max) about 200% basal activity and K(m) of approximately 3 microM for P-gp. In contrast, DL had no significant effect on baseline ATP hydrolysis. L inhibited human P-gp much less than verapamil or cyclosporin A. DL inhibited human P-gp significantly less than L (4 times). DL therefore is not a significant inhibitor of P-gp and should not cause clinical drug interactions with agents that are P-gp substrates.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • ATP-Binding Cassette Transporters / metabolism
  • Adenosine Triphosphate / metabolism
  • Antibiotics, Antineoplastic / pharmacology
  • Cell Line
  • Daunorubicin / pharmacology
  • Flow Cytometry
  • Histamine H1 Antagonists / pharmacology*
  • Humans
  • Hydrolysis
  • Kinetics
  • Loratadine / analogs & derivatives
  • Loratadine / pharmacology*
  • Phosphates / metabolism

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • ATP-Binding Cassette Transporters
  • Antibiotics, Antineoplastic
  • Histamine H1 Antagonists
  • Phosphates
  • Loratadine
  • Adenosine Triphosphate
  • desloratadine
  • Daunorubicin