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US 6,686,338 B1Granted
Enzyme inhibitors for metabolic redirection
AssigneeBoard of Regents of the University of Nebraska
InventorPatrick L. Iversen
Life of this patent
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Abstract
A method is described for improving the pharmacokinetics of a drug in a subject, by co-administering oligomers, preferably PMO's (phosphorodiamidate morpholino oligonucleotides), antisense to RNAs encoding drug-metabolizing enzymes, particularly p450 enzymes. The oligomers reduce production of the drug-metabolizing enzymes, which extends drug half-life and effectiveness and/or decreases drug toxicity.
Claims20
A method of inhibiting metabolism of a drug administered to a mammalian subject, comprising
- co-administering with said drug a morpholino antisense oligomer effective to reduce expression of a cytochrome p450 enzyme that catalyzes metabolism of the drug in said subject, by hybridizing to a target RNA molecule which encodes said enzyme;
- wherein the cytochrome p450 is selected from the group consisting of CYP2B1, CYP2E1, CYP3A2, and CYP3A4;
- and wherein said morpholino oligomer:
- is composed of morpholino subunits, linked together by uncharged phosphorus-containing linkages, one to three atoms long, joining the morpholino nitrogen of one subunit to the 5′ exocyclic carbon of an adjacent subunit, and includes, linked to each subunit, a purine or pyrimidine base-pairing moiety effective to bind, by base-specific hydrogen bonding, to a base in a polynucleotide, and has a base sequence selected from the group consisting of:
- SEQ ID NO:
- 16, for inhibition of CYP2B1, SEQ ID NOs:
- 18-20 and 23, for inhibition of CYP2E1, SEQ ID NOs:
- 24 and 25, for inhibition of CYP3A2, and SEQ ID NOs:
- 35, 46, and 47, for inhibition of CYP3A4.
6 more elements
Dependencies are inferred from the claim text.