MAMMALIAN OLIGOPEPTIDE TRANSPORTERS - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 131

Further studies were established to determine if the high absorption of valacyclovir
was due to carrier-mediated transport. The absorption of acyclovir and valacyclovir
was studied in cynomologus monkey intestinal brush border membrane vesicles,
where the influx of valacyclovir into the vesicles was six- to 10-fold higher than the
influx of acyclovir. 194 Additional studies in Caco-2 cells showed that transport of
valacylovir was seven times higher than acyclovir transport. In rats, L-amino acid
ester analogs of acyclovir show better absorption than D or D-L analogs, indicating
that the transport was also stereoselective. 177
Several studies in Caco-2 and transfected cell lines have shown that valacylovir is
transported by rat and human PepT1, even though the prodrug does not have a peptide
bond. 176 , 181 - 187 Recent work has, however, shown that several additional transporters
may be involved in valacyclovir transport in humans, and that PepT1 may not be
the predominant transporter of this prodrug in humans. Most recently it has been
suggested that valacyclovir transport by PHT1 and hPT1 may also be contributing
absorption pathways. 61 , 188
The absolute bioavailability of acyclovir when 100 mg of oral valacyclovir prodrug
is dosed to healthy human subjects is 54%, compared to only 15 to 20% (200- to 600-
mg doses) after acyclovir was dosed orally. 189 , 190 Larger variability was observed after
dosing of acyclovir than following valacyclovir dosing. The bioavailability of acy-
clovir from orally dosed valacylovir is similar in rats and cynomolgus monkeys. 191 , 192
Over 99% of valacyclovir that is not absorbed is converted to acyclovir.
When valacyclovir is administered orally, there is a slightly less than dose propor-
tional increase in acyclovir exposure and an increase in T max with increasing doses.
The slightly reduced absorption of valacyclovir, with increasing dose is not likely,
due to saturable conversion to acyclovir, because of low urinary recovery of valacy-
clovir, and because the valacyclovir/acyclovir ratio remains the same with increasing
dose. The reduced absorption may be due to saturation of absorption sites along the
gastrointestinal tract. 193 , 194
Although valacyclovir is more soluble than acyclovir (174 mg/mL versus 1.3 mg/
mL), 177 solubility is unlikely to limit absorption of either compound. This is supported
by the fact that many of the other amino acid ester analogs that have been studied also
exhibit improved solubility over acyclovir. However, these analogs have very diverse
bioavailability, probably due to differences in their carrier-mediated transport. 177
6.6. CONCLUSIONS
Figures 6.1 and 6.2 summarize the parallel pathways of permeation and some of the
important factors associated with the mass transfer resistances encountered with each
permeation route for oligopeptides passive and active transport across cell barriers.
It is clear that the passive routes of permeation are very restrictive and limited in the
capacity for proper significant absorption of peptide-based drugs, particularly across
the gastrointestinal epithelium. Based on this, increasing attention has been focused
on developing agents that may be able to traverse these barriers through increasing
their affinity and capacity for peptide transporters. Until recently, most of the attention