PharmPK Discussion - Phase II conjugates in FDA newly-issued draft DDI guidance

• On 18 Apr 2012 at 16:56:59, Yi Gu (gooey1981.aaa.yahoo.com.cn) sent the message
  

  
  The following message was posted to: PharmPK
  
  Dear colleagues,
  
  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
  Shanghai, China
  
  

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