Redirection of drug metabolism using antisense technology.
The cytochrome P450 (CYP) family is the most catalytically versatile component of the phase I oxidation metabolic pathway and participates in the metabolism of a large majority of drugs used in clinical practice. The inhibition of specific enzymes of this family can significantly alter the disposition and toxicity of substrate drugs by reducing and/or redirecting their metabolism. This review discusses the approaches available for CYP inhibition, with particular emphasis on the potential use of antisense phosphorodiamidate morpholino oligonucleotide strategies to inhibit human CYP3A4. Inter-individual variations of 10- to 50-fold have been reported in the activity of CYP3A4 enzyme, which contributes to the metabolism of more than half of all clinically relevant drugs. The application of antisense technology for inhibition of specific CYP enzymes can provide significant therapeutic benefits, including: (i) reduction of first-pass drug metabolism; (ii) reduction in drug dosage; (iii) selective reduction of toxic metabolites; and (iv) increased oral/topical drug bioavailability. The use of antisense morpholino oligonucleotide strategies to target CYP enzymes may result in safer and more uniform therapeutic applications.
Arora
V
V
Research and Development, AVI BioPharma Inc, Corvallis, OR 97333, USA. varora@avibio.com
Iversen
P L
PL
D000595:Amino Acid Sequence; D000818:Animals; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes; D008099:Liver / Q000201:enzymology; D051379:Mice; D018345:Mice, Knockout; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D009025:Morpholines / Q000737:chemistry / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D013873:Thionucleotides / Q000235:genetics / Q000378:metabolism*
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D009025:Morpholines; D016376:Oligonucleotides, Antisense; D013873:Thionucleotides; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human