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I have two questions when I was reading the FDA newly-issued draft DDI guidance
(Feb, 2012). Both of them are related to a similar situation which is about
phase II conjugates.
One is about the UGT substrate identification study. In the Figure 3 in that
guidance which showed the decision tree about evaluation of investigational
drugs as UGT substrates, the precondition is "is glucuronidation responsible for
>=25% of total metabolism". My question here is does the glucuronidation
mentioned here account for sequential metabolism? In other words, for a given
compound, if the direct glucuronidation is negligible while phase I metabolism
is the major clearance pathway for the parent compound, however, glucuronidation
extensively happens to the phase I metabolites and finally the major in vivo
metabolites appear to be the glucuronide conjugates of certain phase I
metabolites. How to deal with this situation? To my understanding, if there is
one major glucuronide conjugate of a phase I metabolite, it should be test the
potential of this phase I metabolite, instead of the parent compound, to be the
UGT substrate. Am I right? But
further, if there is no such one or two glucuronide conjugates of phase I
metabolites are major (>25% of parent exposure), but overall glucuronidation of
the phase I metabolites is significant with respect to the total metabolism of
the parent compound. What should we do next? BTW, my question is also related to
how to calculate the glucuronidation contribution of the total metabolism?
My second question is also related to this kind of situation I proposed, but it
is related to the transporter accounting for clearance. The FDA new guidance
require testing whether the investigational new drug is OAT1 or OCT2 substrate
if renal active secretion is the major clearance mechanism of this drug.
However, if hepatic metabolism is the major clearance mechanism and direct renal
excretion of the parent compound is negligible for a given drug, it seems no
need to test the potential of parent compound to be the OAT1 or OCT2 substrate.
But if for this same compound there is a major phase II conjugate that is
extensively excreted in urine, do we need to test the interaction of such major
phase II conjugate with the renal transporters and how to do it?
I am open and appreciate you can share your opinions.
Yi Gu, PhD
Manager, Drug Metabolism & Pharmacokinetics
Hutchison MediPharma Limited
Building 4, 720 Cai Lun Road, Zhangjiang Hi-Tech Park
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