Inhibition of human cytochrome P450 isoforms by nonnucleoside reverse transcriptase inhibitors.
The capacity of three clinically available nonnucleoside reverse transcriptase inhibitors (NNRTIs) to inhibit the activity of human cytochromes P450 (CYPs) was studied in vitro using human liver microsomes. Delavirdine, nevirapine, and efavirenz produced negligible inhibition of phenacetin O-deethylation (CYP1A2) or dextromethorphan O-demethylation (CYP2D6). Nevirapine did not inhibit hydroxylation of tolbutamide (CYP2C9) or S-mephenytoin (CYP2C19), but these CYP isoforms were importantly inhibited by delavirdine and efavirenz. This indicates the likelihood of significantly impaired clearance of CYP2C substrate drugs (such as phenytoin, tolbutamide, and warfarin) upon initial exposure to these two NNRTIs. Delavirdine and efavirenz (but not nevirapine) also were strong inhibitors of CYP3A, consistent with clinical hazards of initial cotreatment with either of these drugs and substrates of CYP3A. The in vitro microsomal model provides relevant predictive data on probable drug interactions with NNRTIs when the mechanism is inhibition of CYP-mediated drug biotransformation. However, the model does not incorporate interactions attributable to enzyme induction.
Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA.
L L
LL
von Moltke
D J
DJ
Greenblatt
B W
BW
Granda
G M
GM
Giancarlo
S X
SX
Duan
J P
JP
Daily
J S
JS
Harmatz
R I
RI
Shader
D000480:Alkynes; D019380:Anti-HIV Agents / Q000494:pharmacology*; D048588:Benzoxazines; D003521:Cyclopropanes; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D020008:Delavirdine / Q000494:pharmacology; D006801:Humans; D006868:Hydrolysis; D020128:Inhibitory Concentration 50; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D019829:Nevirapine / Q000494:pharmacology; D010078:Oxazines / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D014229:Triazolam / Q000378:metabolism
D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D065607:Cytochrome P-450 Enzyme Inhibitors; D007527:Isoenzymes; D010078:Oxazines; D018894:Reverse Transcriptase Inhibitors; D014229:Triazolam; D003577:Cytochrome P-450 Enzyme System; D019829:Nevirapine; D020008:Delavirdine; C098320:efavirenz