Back to the Top
The following message was posted to: PharmPK
I have heard about Phase III drug metabolism. I am
not sure whether it is a speculation or reality. I
will appreciate if PharmPK members can provide me with
information on this.
Thanks
Ananda
Back to the Top
The following message was posted to: PharmPK
Dear Ananda,
The transport processes responsible of the excretion of compounds into
bile are commonly defined as Phase III reactions. This terminology has
been chosen to describe the sequential steps that determine the PK of
drugs in liver, namely
phase O: uptake of drugs from blood into hepatocytes
Phase I: functionalisation by phase I enzymes (CYP450)
Phase II: conjugation by phase II enzymes (ST, GST, UGT)
Phase III: Excretion via ATP-dependent transporters (mrp2, mdr1...)
Hope this help,
Olivier
Back to the Top
The following message was posted to: PharmPK
Dear Ananda,
Since the relevance of canalicular drug transporters became more and
more
evident, Ishikawa proposed in 1992 the term Phase III drug ELIMINATION
for
the canalicular transport of drugs and drug metabolites from hepatocytes
into bile. (See Ishikawa T, The ATP-dependent glutathione S-conjugate
export
pump. Trends Biochem Sci;1992:463-468) - so you would have Phase I
(oxidation etc.), Phase II (glucuronidation, sulfatation etc.) and
Phase III
elimination of the glucuronides into bile.
Since recent studies furthermore suggest that drug interactions also can
take place at basolateral drug uptake systems, such as for example the
organic anion transporting polypeptides (OATPs, SLC21 superfamily), and
that
these systems might also be rate limiting and determine their
substrates PK,
we took up on this idea and proposed in the discussion section of a
recent
paper (SR Vavricka et al, Interactions of rifamycin SV and rifampicin
with
organic anion uptake systems of human liver. Hepatology. 2002 Jul;
36(1):
164-72) to name basolateral uptake into hepatocytes as Phase 0. It was
therefore suggested that the overall hepatic drug elimination process
should
be divided into four rather than just two or three phases with phase 0
pointing to the basolateral (sinusoidal) uptake processes, phase I
describing the cytochrome P450 dependent oxidation reactions, phase II
meaning drug conjugation reactions and phase III defining the
canalicular
(or basolateral) excretory process.
So to my knowlegde the so called phase III is not metabolism, but
transport.
I hope this clarifies the issue.
Yours sincerely
Karin
Back to the Top
The following message was posted to: PharmPK
Dear Ananda,
I've heard two meanings of phases III metabolism.
1. After conjugation with glutathione (this is a tripeptide and a Phase
II
reaction) the adduct is then cut off (Phase III) by two amino acids
(Glutaminic acid and glycine) leaving only the cysteine behind, which is
called mercapturic acid
2. After conjugation of a drug by glucuronides (Phase II reaction) the
adduct is then recognized by transporters of the liver (eg MRP2) and
then
transproted into the bile (Phase III)
.... but I'm not sure which one (or both) are correct
alle the best
Philip
Dr. Philip Lienau
Schering AG
Research Pharmacokinetics
Tel.: +49 - 30 - 468 - 18507
Fax: +49 - 30 - 468 - 12238
PharmPK Discussion List Archive Index page
Copyright 1995-2010 David W. A. Bourne (david@boomer.org)