Dear Group,Back to the Top
Is it appropriate to extrapolate the clearance from
rodents to humans using allometric approach since there is a reversal
in dark-light cycle observed in rodents compared to humans and the
subsequent impact on ADME has been well documented?
Pharmacokinetic parameters viz., Cmax,Tmax,CL,Vd which are
considered conventionally to be constant in time are proved to be
circadian time dependent. In humans such differences are well
demonstarted for drugs such as Nifedipine, Oral nitrates and
propranolol, which were shown to have a 2 fold higher Cmax and shorter
Tmax after morning compared with evening administration probably
because offaster gastric emptying time and higher gastro intestinal
perfusion in the morning ( Bruguerolle B in Heidelberg Springer-verlag
1992; 371-81).
Microdialysis would then be a bettersampling
technique inorder to monitor ADME with time.Why do we ignore
Chronokinetics as there is no guidelines to lead further? Is it not
necessary to document chronopharmacokinetics for NCEs in laboratory
Rodents?
Regards,
S Syed Mustafa,
Senior Pharmacologist,
Dr Reddy's Research Foundation,
INDIA.
Back to the Top
I do not consider allometric predictions of clearance as a substitute
for chronopharmacokinetic effects on clearance or vice versa. As far as
I am aware these are quite independent causes of variation in clearance
between and within species. So I would suggest using allometric
predictions as a baseline then see if you can detect
chronopharmacokinetic changes in addition.
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
Zealand
email:n.holford.at.auckland.ac.nz tel:+64(9)373-7599x86730 fax:373-7556
http://www.health.auckland.ac.nz/pharmacology/staff/nholford/
Back to the Top
Syed,
So far as I am aware, we do not have to evaluate chronopharmcokinetics
as part of the pre-clinical drug development program in the U.S.,
unless there is a compelling, relevant reason to do so. And remember,
all PK parameters are actually weighted, mean parameters over the
sampling interval. So, hypothetically assume we have a chronological
PK profile over a single-dose profile (IV dosing). CL =
Dose/(AUC(0-infinity). The calculated value of CL is actually a
weighted CL of all values of CL over the period 0-infinity (where
infinity -- as a practical matter --is actually a timecharacteristic
of the drug and experimental conditions). If we had nonlinear PK, then
the CL so calculated would be the mean, weighted CL over the time frame
of the experiment, viz., in both cases, we have a "hybridized" PK
clearance. But this is very common. For example, with high CL drugs
in particular, posture, which affects hepatic blood flow, will
alsochange CL. So, if you change posture in an experiment with a high
clearance drug, you are changing CL during the experiment, e.g., with
nicotine. Again, you get a weighted, mean CL.Best wishes. Harold.
Back to the Top
Dear Nick,
You wrote:
[..]I am aware these are quite independent causes of variation
in clearance between and within species.
Could you clarify 'independent'? Do you mean independent of other
causes of variation in clearance?
If I understood that correctly, couldn't one use assessment of presence/
confirmation of absence of chronopharmacokinetic variation to improve
allometric prediction?
....or at least be aware of possible consequences if present in
laboratory
animals.
Of course this may not be feasible as conducting experiments in a
chronobiological setting require investments, eg. a room on a reversed
L:D cycle, training in handling animals to avoid sleep disturbance etc.
Best regards,
Jeroen
Dear Dr Holford & Pharm PK Group,Back to the Top
As all of us are aware that bright light has
immediate alerting effects in diurnal mammals such as humans whereas
darkness promotes sleep.But nocturnal rodents exhibit the inverse
effects with bright light inducing sleep and darkness increasing
wakefulness.The acute changes in sleep patterns in response to
light-dark in albino rats are reported to be mediated by superior
colliculus- Pretectum (SC-PT).
The rationale behind questioning allometric
approach in predicting human clearance using rodent data was basically
because we usually extrapolate the data that is being derived in
rodentsin bright light ( Sleep cycle ) where clearance is expected to
be lower.When circadian rythm has significant effect on ADME, don't you
think that ideally one must consider these changes before predicting
clearance in Humans? Also we lack guidance with respect to pre-clinical
chrono pharmacokinetics andas far I know we only attempt to explore it
only for cardiovascular and antiasthmatic drugs where time dependent PD
is essential. I welcome the suggestions on this issue.
With Regards,
S Syed Mustafa,
Senior Pharmacologist,
Dr Reddy's Research foundation,
Bollaram Road,Miyapur,
Hyderabad-500049.
INDIA
Back to the Top
syed mustafa wrote:
" The rationale behind questioning allometric
approach in predicting human clearance using rodent data was basically
because we usually extrapolate the data that is being derived in
rodents in bright light ( Sleep cycle ) where clearance is expected to
be lower.When circadian rythm has significant effect on ADME, don't you
think that ideally one must consider these changes before predicting
clearance in Humans?
"
You seem to be saying that allometric prediction is a synonym for
predicting clearance in humans. Allometric scaling is just one of many
identifiable covariates that should be considered when attempting to
predict human clearance from other species e.g. differences in CYP
expression. If you want to test if animals with a different sleep-wake
cycle have predictable differences in clearance then go ahead and do
it. But don't forgot to include allometric predictions as well because
there is absolutely no doubt that clearance increases with body mass.
"Elassaiss-Schaap, Jeroen [PRDBE]" wrote:
"You wrote:
[..]I am aware these are quite independent causes of variation
in clearance between and within species.
Could you clarify 'independent'? Do you mean independent of other
causes of variation in clearance?
"
I consider that there is a component of clearance variation that is
predictable on theoretical and very strong empirical grounds. While
there may be some correlation between body size and other causes of
clearance variation (e.g. age) I believe that one should always start
with allometry as the base model (with fixed allometric coefficients)
and then look for empirical associations with factors such as age and
sleep-wake cycle. So for pragmatic reasons I consider the allometric
component of clearance differences to be independent of other causes.
"If I understood that correctly, couldn't one use assessment of
presence/
confirmation of absence of chronopharmacokinetic variation to improve
allometric prediction?
"
Allometric prediction relies only on body mass. If there is an
association beween body mass and chronopharmacokinetic variation then I
would treat this as an empirical additional component to improve the
prediction of clearance but it would not change the allometric
prediction.
Nick
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
Zealand
email:n.holford.-a-.auckland.ac.nz tel:+64(9)373-7599x86730 fax:373-7556
http://www.health.auckland.ac.nz/pharmacology/staff/nholford/
Back to the Top
Dear Syed, Nick
Now that as you say chronopharmacokinetics has a role
to play then lets look beyond allometric approach and
try to find a solution?
Lets propose other better alternatives and do not
stuck to proving the point on one?
Dr.Nandu Dhabale
---
Dear Syed and all,
how about reversing the light dark cycle and then
perform the experimnts?
when we think this we should think of all variables.
Has any body done this earlier and reported ?
How many days will it take for animals to adapt to the
changed-reversed light cycle?
if animals are not kept in reversed light cycle since
birth then how muh time will it take to adapt reversed
cycle?
Dr.Nandu Dhabale
Back to the Top
Dear Nandu,
You wrote:
"how about reversing the light dark cycle and then
perform the experimnts?"
I would say that is the only way it can be feasibly done,
otherwise the manpower requirements are too high. Do not
underestimate the costs of keeping additional vivaria, though.
One also must take care not to disturb animals too much
i.e. by putting lights on, or to stress them by handling -
this requires additional training and efforts for the
lab technicians.
"How many days will it take for animals to adapt to the
changed-reversed light cycle?"
Normally one would take 14 days to let animals adapt to
a reversed light/dark cycle. Unfortunately, I do
not have references for that, it's more like an accepted
period in the field. When setting up such an approach
in a laboratory, I would recommend recording diurnal
rhythms (measure either drinking, running wheel,
locomotor activity or similar) to monitor reversal of
the animal's behaviour. Keep in mind masking effects,
i.e. light will inhibit activity in itself while the
internal clock is sending an 'active' signal.(*1)
"if animals are not kept in reversed light cycle since
birth then how muh time will it take to adapt reversed
cycle?"
Depends on the species - light entrainment is
something that starts a species-dependent period
after birth. Typical young adults entrain just fine.
Best regards,
Jeroen
(*1) Note: theoretically, light may have a direct (ie. not
directly steered by internal rhythm) effect on relevant physiological
parameters.
The correct terminology for 'internal clock' as used here
is 'circadian pacemaker'. For real theoretical background
reading I can recommend the "Daan / Pittendrigh" papers
(http://www.cbt.virginia.edu/cbtdocs/classicPapers.html).
Dear Dr Nandu and PK Group,Back to the Top
"Dr Nandu wrote
....how about reversing the light dark cycle and then
perform the experiments?"
Ibelieve many of us must havelearnt that the circadian
system in mammals is controlled by three signal pathways.
1. A primary pacemaker located in the suprachiasmatic nucleus of the
hypothalamus which is responsible for generating oscillatory signal
with a period close to 24 hr
2.Output pathways of the central pacemaker
3.Retino-hypothalamic pathway, a direct pathway from the retina.
In addition to the photic input pathway, there are
non-photic pathways providing information to the central clock from
the mid brain raphe nuclei ( J Neurosci 1996,16:2097-2111 and Ann Med
1999,31 :12-33)
In response to external stimuli which may trigger the
activity of the nocturnal rodents for instance pain associated with the
retro orbital bleeding at successive time points (Despite of
anesthesia; Anesthetic ether itself may alter the CYP expression)and
the subsequent shock perceived by the animals may cause a phase delay
since there is a evidence from hamster studies which were subjected to
immobilization during the begining of the usual active period reulted
in the phase delays of the rhythms of locomotor activity.Not much
extensive studies in response to artificial dark-light reversal and
ADME have been reported on rodents.
But certainly one can think of monitoring onset of
Melatonin and Thyrotropin ( Hormonal biomarkers) in blood in order to
conlcude such Phase delays as well as the reversal of dark-light cycle
in rodents, Hamsters, Cats etc., Also one can go for cortisol
estimation in blood as there's an increased secretion in night cycle
(in rodents) inorder to meet the metabolic challenges of the day.Hope
this helps.
With best wishes,
S Syed Mustafa,
Senior Pharmacologist,
Dr Reddy's Research Foundation,
Bollaram Road, Miyapur,
Hyderabad-500049 INDIA
Back to the Top
Hi everybody,
about chronokinetics, it is considered that in about 15 days light/dark
cycle is reversed in rats, however we have done chronokinetic studies
on
ceftriaxone and norfloxacin without cycle reversing, that is, working
the 24
hs, in light and dark, and we have found differences mainly in both
antimicrobials elimination
marcela rebuelto
buenos aires, argentina
marcela rebuelto
Back to the Top
Dear marcela rebuelto,
I would be highly obliged if you or any one can give
me a reference which studies the time taken for
reversal of light dark cycle in laboratory animals.
I intend to use rats to study behavioral
parameters.However I am unable to finalise for how
many days I should reverse the cycle so that rats get
adapted to new cycle?
please advice..
Thank you.
Dr.Nandu Dhabale
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