Effect of prototypical inducing agents on P-glycoprotein and CYP3A expression in mouse tissues.
P-glycoprotein (P-gp) and CYP3A have considerable overlap in inducers in vitro. Characterizing P-gp induction in vivo and potential coregulation with CYP3A are important goals for predicting drug interactions. This study examined P-gp expression in mouse tissues and potential coinduction with CYP3A following oral treatment with 1 of 7 prototypical inducing agents for 5 days. P-gp expression in brain or liver was not induced by any treatment as determined by Western blot, whereas dexamethasone, pregnenolone-16alpha-carbonitrile (PCN), St. John's wort (SJW), and rifampin induced hepatic CYP3A expression. In intestine, rifampin and SJW induced P-gp expression 3.7- and 1.6-fold and CYP3A 3.5- and 2.4-fold, respectively, whereas dexamethasone and PCN induced CYP3A only. These observations suggest that P-gp in mouse small intestine is inducible by some, but not all, CYP3A inducers, whereas P-gp expression in liver or brain is not readily induced. Intriguingly, rifampin and SJW, both activators of the human pregnane X receptor (PXR), induced CYP3A in both liver and intestine but induced P-gp only in intestine, whereas PCN, an activator of murine PXR, did not induce P-gp in any tissue. Rifampin disposition was evaluated, and hepatic exposure to rifampin was comparable to intestine; in contrast, brain concentrations were low. Overall, these observations demonstrate that P-gp induction in vivo is tissue-specific; furthermore, there is a disconnect between P-gp induction and CYP3A induction that is tissue- and inducer-dependent, suggesting that PXR activation alone is insufficient for P-gp induction in vivo. Tissue-specific factors and inducer pharmacokinetic/pharmacodynamic properties may underlie these observations.
Matheny
Christopher J
CJ
Division of Drug Delivery and Disposition, School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA.
Ali
Rabia Y
RY
Yang
Xiaodong
X
Pollack
Gary M
GM
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000737:chemistry / Q000187:drug effects / Q000235:genetics*; D000199:Actins / Q000187:drug effects / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000187:drug effects / Q000235:genetics*; D015153:Blotting, Western / Q000379:methods; D001921:Brain / Q000166:cytology / Q000187:drug effects; D051544:Cytochrome P-450 CYP3A; D003907:Dexamethasone / Q000494:pharmacology; D004334:Drug Administration Schedule; D004790:Enzyme Induction / Q000187:drug effects / Q000235:genetics*; D005786:Gene Expression Regulation; D020902:Hypericum / Q000737:chemistry; D007421:Intestine, Small / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007440:Intubation; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009543:Nifedipine; D010089:Oxidoreductases, N-Demethylating / Q000187:drug effects / Q000235:genetics*; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology; D000077297:Pregnane X Receptor; D011285:Pregnenolone Carbonitrile / Q000494:pharmacology; D020033:Protein Isoforms / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D011987:Receptors, Steroid / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D012293:Rifampin / Q000378:metabolism / Q000494:pharmacology; D013629:Tamoxifen; D013997:Time Factors
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000199:Actins; D010936:Plant Extracts; D000077297:Pregnane X Receptor; D020033:Protein Isoforms; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D013629:Tamoxifen; D011285:Pregnenolone Carbonitrile; D003907:Dexamethasone; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D009543:Nifedipine; D012293:Rifampin