Abstract
The purpose of this study was to evaluate loratadine, desloratadine, and 3-OH-desloratadine as inhibitors of certain human liver cytochrome P-450 enzymes. Pooled human liver microsomes were used to determine whether loratadine, desloratadine, and 3-OH-desloratadine were inhibitors of cytochrome P-450 (CYP) 1A2, 2C9, 2C19, 2D6, and 3A4. Loratadine did not inhibit CYP1A2 or CYP3A4 at concentrations up to 3829 ng/ml, which is approximately 815-fold greater than the expected maximal human plasma concentration (4.7 ± 2.7 ng/ml) following the recommended dose of 10 mg/day. Loratadine inhibited CYP2C19 and CYP2D6 with IC50 values of approximately 0.76 μM [291 ng/ml; Ki ≅ 0.61 μM (234 ng/ml)] and 8.1 μM [3100 ng/ml; Ki ≅ 2.7 μM (1034 ng/ml)], respectively, which are approximately 62 and 660 times the expected loratadine therapeutic exposure concentration. Neither desloratadine nor 3-OH-desloratadine inhibited CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 greater than 25% at concentrations of 3108 or 3278 ng/ml, respectively. These results suggest that loratadine and the active metabolites desloratadine and 3-OH-desloratadine are unlikely to affect the pharmacokinetics of coadministered drugs which are metabolized by these five cytochrome P-450 enzymes.
Footnotes
- Abbreviations used are::
- LOR
- loratadine
- DL
- desloratadine
- G6P
- glucose 6-phosphate
- G6Pdh
- glucose-6-phosphate dehydrogenase
- Cmax
- maximum plasma concentration
- CYP
- cytochrome P-450
- HPLC
- high-performance liquid chromatography
- IC50
- concentration at half-maximal enzyme inhibition
- 3-OH-DL
- 3-hydroxydesloratadine
- Received January 22, 2001.
- Accepted May 25, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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