Asian Journal of Pharmacodynamics and Pharmacokinetics

Special Report. Asian Journal of Pharmacodynamics and Pharmacokinetics 2009; 9(1):5-9
Dosing:
For intravenous dosing, drug concentrations at
the eliminating organ will always be relatively low
due to the diluting effects of volume of distribution,
as compared to concentrations of drug in the
intestine. Therefore, saturation of transporters (and
enzymes) will be minimal, if at all, and solubility
considerations will be unimportant when
measurable systemic concentrations of the drug are
achieved.
• High extraction ratio drugs, where
clearance approaches blood flow, are mainly limited
to Class 1 compounds.
• Post intestinal absorption and following
intravenous dosing, both uptake and efflux
transporters can be important determinants of the
disposition for Classes 2, 3, and 4 compounds.
• Biliary secretion of parent drug can be an
important component of disposition for Classes 3
and 4 compounds.
• Renal elimination of Classes 3 and 4
compounds can be affected by both uptake and
efflux transporters.
Potential Drug-Drug Interactions Predicted
by BDDCS:
Class 1: Only metabolic in the intestine and
liver
• Drug-drug interactions for Class 1
compounds will be primarily metabolic, with
transporter-enzyme interplay only becoming
important for those drugs where high permeability
is a result of rapid transporter uptake rather than
high Log P.
Class 2: Metabolic, efflux transporter and efflux
transporter-enzyme interplay in the
intestine. Metabolic, uptake
transporter, efflux transporter and
transporter-enzyme interplay in liver.
• Drug-drug interactions are not limited to
enzymatic processes but can frequently be mediated
by transporter interactions and often involve
transporter-enzyme interplay for Class 2
compounds.
• Following oral dosing, major significant
interactions will occur for Class 2 drugs that are
substrates for both intestinal enzymes (e.g., CYP3A,
UGTs) and intestinal apical efflux transporters (e.g.,
P-glycoprotein, MRP2, BCRP).
• The enzyme-efflux transporter interplay
that is so important in the intestine will not be as
significant in the liver (and the kidney) due to the
reverse order in which drug molecules encounter
the two proteins.
• Inhibition of hepatic uptake transporters
can lead to significantly increased systemic drug
concentrations for Class 2 compounds
Class 3 and 4: Uptake transporter, efflux
transporter and uptake-efflux transporter interplay.
Inhibition of hepatic and renal uptake
transporters can lead to significant increases in the
systemic concentration of Classes 3 and 4
compounds.
Conclusions
The interplay between transporters, both influx
and efflux, and metabolic enzymes in the intestine
and the liver could differ depending on the drug’s
solubility and permeability characteristics as
reflected in the Biopharmaceutical Classification
System (BCS). Although BCS has had a marked
effect in decreasing the regulatory burden by
allowing a waiver of in vivo bioequivalence studies
for a limited number of Class 1 drugs, little
predictive use has been made of Classes 2, 3, and 4
in the BCS categorization. In general, BCS Classes
1 and 2 are highly metabolized, whereas BCS
Classes 3 and 4 drugs are primarily excreted
unchanged via the biliary or renal routes. Therefore,
changing the permeability component to a route of
elimination component in a Biopharmaceutics Drug
Disposition Classification System (BDDCS) will
facilitate predictions, markedly expand the number
of Class 1 drugs eligible for waiver of in vivo
bioequivalence studies, and provide new insight. It
may be easier to determine classification based on
major routes of elimination than upon permeability;
an extent of metabolism criterion for waiver of in
vivo bioequivalence studies; and how predictive
algorithms may be developed using only in vitro or
in silico methods to facilitate class assignment in
BDDCS. A further advantage of BDDCS is that a
preliminary class assignment for NMEs may be
obtained from a metabolism measure in human
hepatocytes, prior to in vivo studies in humans.
Understanding transporter-enzyme interactions in
terms of the permeability and solubility of drug
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