This study investigated the effects of nefazodone (NFZ) and trazodone (TZD)
on P-glycoprotein (P-gp) activity and expression in cell culture. NFZ and
TZD showed no differential transport between the basolateral to apical and
apical to basolateral direction across Caco-2 cell monolayers. Transport in
either direction was not affected by verapamil. NFZ was a potent inhibitor
(IC50 = 4.7 muM) of rhodamine123 (Rh 123)B to A transport across Caco-2 ce
ll monolayers, while TZD had minimal effect. Following 72-hour exposure of
LS180V cells to NFZ and TZD (10 muM), a twofold increase in immunoreactive
P-gp was observed. Rh123 accumulation into these cells was reduced to 65% a
nd 74% of control by NFZ and TZD (1 a muM), respectively. It was concluded
that differential rates of transport of NFZ and TZD in Caco-2 cells were no
t evident. However, NFZ is an inhibitor of P-gp activity at clinically rele
vant in vivo concentrations and may have the potential to increase bioavail
ability of coadministered compounds that are substrates far transport. Conc
entrations of NFZ and TZD achieved in the intestine after chronic oral dosi
ng may induce P-gp expression and reduce absorption of coadministered drugs
.