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

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Wang EJ, Casciano CN, Clement RP, Johnson WW

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

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

PubMed ID

11454724 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Desloratadine	P-glycoprotein 1	Protein	Humans	Unknown	Inhibitor	Details
Loratadine	P-glycoprotein 1	Protein	Humans	No	Substrate Inhibitor	Details

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Desloratadine	P-glycoprotein 1	IC 50 (nM)	43000	N/A	N/A	Details
Loratadine	P-glycoprotein 1	IC 50 (nM)	11400	N/A	N/A	Details
Verapamil	P-glycoprotein 1	IC 50 (nM)	4200	N/A	N/A	Details