METABOLITE KINETICS

Diky Mudhakir

School of Pharmacy
Institut Teknologi Bandung
Introduction

Any metabolite can be pharmacologically active &

contribute to the overall efficacy of the drug interest.
Ex. Atorvastatin (parent) hydroxylated metabolite
Clopidogrel (parent) thiol metabolite

The use of information on active metabolites:

To comprehend the pharmacokinetic-
pharmacodyamic (PK-PD) relationships of drugs
To provide important guidance to their use in the
clinic
1. Concepts & Principles
a. General considerations
Linear pharmacokinetics is assumed
The metabolite formed is assumed not to
convert back to the parent drug
There is no reversible metabolism
To avoid conversions between a drug & a
metabolite due to a difference in MW in
molar units
b. Formation Clearance vs. Elimination Clearance of
Metabolite
The kinetics of a metabolite in the systemic
circulation is governed by both its formation
and its disposition
Appearance of metabolite in circulation is a
function of enzyme activities & permeation
Sequential metabolism & excretion into
excreta (ex. Bile & urine)
@ affect the conc. of the metabolite formed
@ impacting on the rate & extent of metabolite
A simplified model for metabolic kinetics
c. Major circulating metabolite vs Major metabolic
pathway
A major circulating metabolite is the metabolite
that represents a substantial portion (ex. 10%)
of drug-related components in circulation.
A major metabolic pathway is the route that
constitutes a major fraction of biotransformation
pathways.
Conceptual difference between a major circulating
metabolite & the product of a major metabolite of
biotrasformation
c. Formation Rate-Limited vs. Eliminated Rate-
Limited Metabolite Kinetics
The concentration time profile of a metabolite is
governed by the formation & elimination
processes
Clearance & volume distribution of the parent
drug and metabolite are important determine
half-life (or elimination rate constant)
Effect s of the rate-limiting step in metabolite kinetics

Formation rate-limited Elimination rate-limited

Neither of steps is rate-limiting
Effect s of the rate-limiting step in metabolite kinetics
Formation rate-limited
Elimination rate-limited
PRE-SYSTEMICALLY FORMED VS. SYSTEMICALLY FORMED
METABOLITE

Pre-systemically formed metabolites: metabolites produced during

the first pass after oral administration involves metabolism in
the gut & liver

Systemically formed metabolites: metabolites that are produced

during general circulation such as after intravenous dosing or
subsequent organ passes after reaching systemic circulation
following oral administration
Harga M/P AUC ratio
Intravena Oral
Subjek 4 0,13 0,43
Subjek 8 0,19 1,20
IN SITU-GENERATED VS EXOGENOUSLY DOSED METABOLITE

In-situ metabolite

Exogen metabolite
 Some different behave of pharmacokinetics
between in-site metabolite & exogenously
dosed metabolite

It affects pharmacotherapy/toxicology of
those metabolites
 Metabolites formed are more hydrophilic than
parent drug extent of distribution is different

Ability of exogenous metabolite in accessing

influx/efflux transporters & enzymes. In-situ
generated metabolite its metabolism affected in
the presence of parent drug

Formation rate-limited metabolite kinetics: different

kinetics between in situ-generated metabolite &
exogenously dosed metabolite. Kinetics of in-situ
metabolite is governed by kinetics of parent drug
SEQUENTIAL METABOLISM

Primary metabolite is formed by sequential metabolism to produce

secondary metabolite
Equation:

fm = fraction of total body clearance of parent drug forming primary

metabolite
fm(m1) = fraction of primary metabolite forming secondary
metabolite.
Equation of metabolic ratio:
Ae, Ae(m1), Ae(m2): amounts of parent drug, primary metabolite and
secondary metabolite in excreta

Similarly, equation:

It is valid only if AUC is total area of the curve from time zero to infinity
& recovery of parent drug & metabolites is complete in excreta
EFFECT OF INHIBITION AND INDUCTION ON
METABOLITE KINETICS

In drug-drug interaction study Cmetabolit related

with clearance pathway is often determined

Clf Css & AUC metabolit

LOGIC
Clf Css & AUC metabolit
?
OBSERVATION OF CHANGING THE FORMATION
CLEARENCE
By comparing ratio of AUC M/P or ratio of Css in the presence &
absence of inhibitor or inducer

Assuming no change in the Cl(m) in the presence of an inhibitor or

inducer:
M/P AUC ration in the presence & absence of inhibitor or inducer:

It is indicates that a change in the M/P AUC ratio directly reflects

the change in the metabolite formation clearance

The metabolic ratio in excreta can be used to assess alteration in

the formation clearance of metabolite:
Assuming no change in Cle (renal or biliary clearance) of parent
drug in the presence & absence of inhibitor or inducer:

Again, like the M/P AUC ratio, a change in metabolic ratio directly
reflects the change in the metabolite formation clearance
The higher the inhibition of metabolite Clf, metabolite AUC is decreased
The higher fm value, the less affected the metabolite AUC, even when
the fm is inhibited by 100%

The higher fm, the more affected the parent AUC

The change in M/P ratio or metabolic ratio inversely related to extent
of inhibition of Clf & independent of the fm

This change results from the alteration in the parent AUC or Ae

Metabolite AUC or Ae(m) will be unchanged assuming that inhibitor or
inducer does not affect the elimation clearance of metabolite
DETERMINATION OF FORMATION & ELIMINATION
CLEARANCE OF METABOLITE
Condition 1: Synthetic metabolite standard is available

Administration: intravena
CLm is calculated as that for CL intravena
Calculation of CLf :

Kinetics of disposition may be different from

metabolite that formed naturally
Condition 2:
Metabolite standard is not available/ not
possible by i.v administration
CL(m) and CLf are determined from parent drug
Data of parent drug and its metabolite are available in
plasma and excreta.
Calculataion of CLm :

Assumption: All produced metabolites enter systemic

circulation and no sequential metabolit occured
The equation above is accurate if metabolite is
produced in liver/gut and eliminated through urine
excretion in unchanged form
If :
There is significant sequential metabolism value of
CL(m) < than its actual due to Ae(m) amount of all
eliminated metabolite
Metabolite produced in liver and gut directly
eliminated via bile secretion value of CL(m) > actual
CL(m) since metabolite in the bile comes from liver.
Thus, value of Ae overestimate CL(m) is too large
Calculation of CLf comparing M/P AUC or ratio of Css
Condition 3:
If the form of metabolite representing major pathway
from clearance metabolite of parent drug
Calculation of CLf :

Assumption : recovery of parent drug & its metabolite

are complete and there is no sequential metabolism.
Excretory clearance of parent drug =
amount of parent drug in excreta
AUC plasma
If CLf has known CLm can be calculated from M/P
AUC or ratio Css
Condition 4 :
If information of metabolite is not available in
plasma
CLf can only be estimated, CLm is not possible
Calculation of CLf :

Assumption: Recovery of metabolite in excreta is complete and no

sequential metabolism.
If recovery of metabolite from excreta is not complete value of
CLf < actual CLf
Additional condition: if drug administered orally, it is assumpt that
metabolite is formed after parent drug enter to the systemic
otherwise CLf > actual CLf
Calculation of CLf

Assumption: recovery of parent drug and its metabolite are

complete and no sequential metabolism.
Condition 5: Sequential Metabolism is occured

Plasma & excreta data of parent drug, primary metabolite, secondary

metabolite must be available.
Calculation of CLf(m1), CLe(m1) & CL(m1):

Assumption:
Primary metabolit primer is produced in the body & totally exist in
the systemic
No sequence metabolism for secondary metabolite
Recovery metabolite in excreta is complete
 CLf > actual CLf
Secondary metabolite can be locally formed in liver at the
same time as the form of primary metabolite
CLe > actual CLe, if bile secretion is part of clearance excretion
pathway of primary metabolite
If CL(m1) has known CLf of primary metabolite can be
calculated M/P AUC or ratio of Css
Condition 6:
Sequential metabolism occurred, but the data of
primary metabolite in plasma is low
CLf can be calcuated, but not for CL(m)

Assumption: there is no sequential metabolism of

secondary metabolite and recovery metabolite in
excreta is complete