A human immunodeficiency virus protease inhibitor is a novel functional inhibitor of human pregnane X receptor.
Drug-drug interactions involving induction of cytochrome P450 enzymes (P450s) can lead to loss of drug efficacy. Certain drugs, particularly those used to treat mycobacterial and human immunodeficiency virus (HIV) infections, are especially prone to induce P450s. During studies to examine drug-interaction potential of compounds in cultured human hepatocytes, exposure with (S)-1-[(1S,3S,4S)-4-[(S)-2-(3-benzyl-2-oxo-imidazolidin-1-yl)-3,3-dimethyl-butyrylamino]-3-hydroxy-5-phenyl-1-(4-pyridin-2-yl-benzyl)-pentylcarbamoyl]-2,2-dimethyl-propyl-carbamic acid methyl ester (A-792611), a novel HIV protease inhibitor (PI) previously under investigation for the treatment of HIV infection, resulted in significant down-regulation of constitutive CYP3A4 expression. Furthermore, coadministration of A-792611 was found to attenuate CYP3A4 induction mediated by known inducers rifampin and efavirenz. A-792611 also attenuated the rifampin and ritonavir-mediated activation of the human pregnane X receptor (PXR) in luciferase reporter assays. Microarray analysis on cultured human hepatocytes revealed that A-792611 treatment down-regulated the expression of PXR target genes CYP3A4, CYP2B6, CYP2C8, and CYP2C9, whereas there was a lack of inductive effect observed in treated rat hepatocytes. A-792611 did not interact with other ligand-activated nuclear receptors that regulate P450 expression such as constitutive androstane receptor, farnesoid X receptor, vitamin D receptor, and peroxisome proliferator-activated receptor alpha. These data suggest that A-792611 is a functional and effective human PXR inhibitor. Among the class of HIV-PIs, which are typically PXR activators, A-792611 seems to have a unique property for PXR antagonism and could be a useful tool for studying nuclear receptor pathway regulation.
Healan-Greenberg
Christine
C
Abbott Laboratories, Global Pharmaceutical Research and Development, Abbott Park, Illinois 60064-6104, USA.
Waring
Jeffrey F
JF
Kempf
Dale J
DJ
Blomme
Eric A G
EA
Tirona
Rommel G
RG
Kim
Richard B
RB
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis / Q000235:genetics; D002478:Cells, Cultured; D000090702:Constitutive Androstane Receptor; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D004151:Dipeptides / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis / Q000235:genetics; D047493:PPAR alpha / Q000378:metabolism; D000077297:Pregnane X Receptor; D011725:Pyridines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D018167:Receptors, Calcitriol / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D011987:Receptors, Steroid / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019438:Ritonavir / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D000099150:Receptor, Farnesoid X-Activated
D001189:Aryl Hydrocarbon Hydroxylases; D000090702:Constitutive Androstane Receptor; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A; D004268:DNA-Binding Proteins; D004151:Dipeptides; D017320:HIV Protease Inhibitors; D010089:Oxidoreductases, N-Demethylating; D047493:PPAR alpha; D000077297:Pregnane X Receptor; D011725:Pyridines; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D019438:Ritonavir; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C520593:methyl 1-(5-(2-(3-benzyl-2-oxoimidazolidin-1-yl)-3,3-dimethylbutanamido)-4-hydroxy-6-phenyl-1-(4-(pyridin-2-yl)phenyl)hexan-2-ylamino)-3,3-dimethyl-1-oxobutan-2-ylcarbamate; C585599:CYP2B6 protein, human; C510163:CYP3A4 protein, human