Evaluation of the interaction of loratadine and desloratadine with P-glycoprotein.
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.
Wang
E J
EJ
Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, 144 Route 94, Lafayette, New Jersey 07848, USA.
Casciano
C N
CN
Clement
R P
RP
Johnson
W W
WW
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D002460:Cell Line; D003630:Daunorubicin / Q000494:pharmacology; D005434:Flow Cytometry; D006634:Histamine H1 Antagonists / Q000494:pharmacology*; D006801:Humans; D006868:Hydrolysis; D007700:Kinetics; D017336:Loratadine / Q000031:analogs & derivatives / Q000494:pharmacology*; D010710:Phosphates / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000903:Antibiotics, Antineoplastic; D006634:Histamine H1 Antagonists; D010710:Phosphates; D017336:Loratadine; D000255:Adenosine Triphosphate; C121345:desloratadine; D003630:Daunorubicin