PT  - JOURNAL ARTICLE
AU  - Baron, Jens M.
AU  - Goh, Lay Beng
AU  - Yao, Denggao
AU  - Wolf, C. Roland
AU  - Friedberg, Thomas
TI  - Modulation of P450 CYP3A4-Dependent Metabolism by P-glycoprotein: Implications for P450 Phenotyping
DP  - 2001 Feb 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 351--358
VI  - 296
IP  - 2
4099  - http://jpet.aspetjournals.org/content/296/2/351.short
4100  - http://jpet.aspetjournals.org/content/296/2/351.full
SO  - J Pharmacol Exp Ther2001 Feb 01; 296
AB  - Some compounds used for phenotyping of cytochrome P450s are substrates of P-glycoprotein (pgp). It is likely that in these cases, the level of pgp modulates the metabolism of in vivo probes. To address this important issue, we have analyzed the effects of pgp on CYP3A4-mediated reactions in two newly established cell lines (3A4/HR/MDR−and 3A4/HR/MDR+), which express CYP3A4 in the absence and presence of pgp, respectively. In cultured cells, the presence of pgp increased the apparent K m for the 6β-hydroxylase activity of CYP3A4 toward testosterone and cortisol by a factor of 1.7 and 4, respectively. These steroids are poor and good substrates of pgp, respectively, and cortisol 6β-hydroxylase has been frequently used as an in vivo probe for CYP3A4. Interestingly, we also found that pgp modulated the inhibition of CYP3A4-mediated metabolism by several compounds in intact cells. Although quinidine inhibited testosterone 6β-hydroxylase activity in membranes or in intact cells that expressed recombinant CYP3A4 in the absence of pgp, low concentrations of this compound increased CYP3A4 activity in intact cells that expressed pgp. These results imply that pharmacokinetic drug-drug interactions involving CYP3A4 can be influenced by pgp.