P334 Interaction of penciclovir with renal drug transporters

Adrienne Natrillo , Drug Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research Inc., East Hanover, NJ
Arpine Vapurcuyan , Dmpk, Novartis Institutes for BioMedical Research Inc., East Hanover, NJ
Yaofeng Cheng , Dmpk, Novartis Institutes for BioMedical Research Inc., East Hanover, NJ
Ryan Pelis , Dmpk, Novartis Institutes for BioMedical Research Inc., East Hanover, NJ
Penciclovir is the active drug of famciclovir, which is used to treat herpes virus.  Penciclovir is primarily cleared from the body via renal excretion, a process that involves robust active proximal tubular secretion.  Thus, we expected that renal drug transporters, including organic anion transporters (OATs), urate transporter 1 (URAT 1), organic cation transporter 2 (OCT2), multidrug and toxin extrusion transporters (MATEs) and multidrug resistance-associated proteins (MRPs) could be important in mediating proximal tubular secretion of penciclovir.  The interaction of [3H]penciclovir as a substrate of renal drug transporters was studied either in human embryonic kidney (HEK) cells stably expressing the individual transporters (OAT1, OAT2, OAT3, OAT4, OCT2, MATE1, MATE2K and URAT1) or in inside-out membrane vesicles (MRP2 and MRP4).  Of the renal uptake transporters tested (OAT1, OAT2, OAT3 and OCT2), only OAT2 supported active penciclovir transport.  The uptake of penciclovir into HEK cells stably expressing OAT2 was ~20-fold higher than in cells not expressing the transporter.  The Jmax and Km value associated with OAT2-mediated penciclovir transport were 284 ± 10 µM and 6.7 ± 0.58 nmol·mg protein-1·min-1, respectively.  Of the efflux transporters tested (OAT4, MATE1, MATE2K, URAT1, MRP2 and MRP4), only MRP4 appeared to transport penciclovir; penciclovir transport was ~2-fold higher in the presence versus absence of ATP.  These data suggest that renal tubular secretion of penciclovir involves a limited number of drug transporters.