A Mathematical simulation to explain the coordinated functions of efflux and metabolism limiting the transport of anti-HIV agents across Caco-2 cells.
OBJECTIVE
The purpose of this study was to simulate a mathematical model that explains the coordinated function of P-glycoprotein (P-gp) and/or CYP3A4 in human intestinal enterocytes. In addition, this study aimed to determine the efflux interactions of anti-HIV protease inhibitors.


METHODS
Human colon carcinoma-derived Caco-2 cells were selected as a model system to evaluate the effects of P-gp-mediated efflux of HIV protease inhibitors. Anti-HIV agents ritonavir and saquinavir were selected as model drugs to determine efflux interactions. An absorption-metabolism classification system is hence proposed based on substrate specificities of drugs toward P-gp and/or CYP3A4 and their probable interactions with other compounds.


RESULTS
Enhanced apical to basal (A-B) ritonavir transport was observed on coadministration of saquinavir. Saturable, concentration-dependent inhibition of ritonavir efflux from Caco-2 monolayers was also observed with saquinavir. The IC(50) values of ritonavir (as a self-inhibitor) and saquinavir from dose-response curves, estimated by fitting the data to nonlinear equations, were found to be 7.15 and 33.2 micromol/L, respectively. The respective K(i) values determined were 8.5 and 28.91 micromol/L. The experimentally obtained K(i) values decreased in the close approximation with the IC(50) values.


CONCLUSIONS
Proposed mathematical simulations may prove to be a useful tool in predicting drug interactions by inhibition of P-gp mediated efflux and CYP3A4-mediated metabolism.
Wyeth Research, 401 N Middletown Rd, Pearl River, NY 10965, USA.
Jignesh
J
Patel
Azher
A
Hussain
Dhahanjay
D
Pal
Ashim K
AK
Mitra
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D001693:Biological Transport, Active; D018938:Caco-2 Cells; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004347:Drug Interactions; D020895:Enterocytes / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000493:pharmacokinetics*; D006801:Humans; D008954:Models, Biological; D019438:Ritonavir / Q000493:pharmacokinetics; D019258:Saquinavir / Q000493:pharmacokinetics; D014316:Tritium
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D017320:HIV Protease Inhibitors; D014316:Tritium; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D019258:Saquinavir; D019438:Ritonavir