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I am expecting your comments on the issue of difference in
We outsourced NCE PK studies at two different CRO's to understand
B.Dog PK parameter. These studies were carried out at 15 mg/kg by IV
At one CRO-the t1/2 was observed 5-6 hr while, at others it was 10-11
The only difference for both studies was wt difference10-12 kg vs.
Hoping for your suggestions.
Wockhardt Research Centre, Aurangabad
[Could this be a pharmacogenomic example ;-) different breeds? - db]
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Dear Dr. Patil,
It is possible that one or more of the following may be involved:
1 - Difference in age of animals, based on the weights provided
2 - Body fat composition (was Vd different since this was IV)
3 - two different populations of dogs, within the breed used (I assumed
4 - Breed differences, such as between lab raised beagles and lab
5 - Sex effect, different sexes or different % between studies
6 - Analytical technique allowing for lower concentrations and
detection for a longer period to make determination of a long t1/2.
There are probably other issue that may have a role, but this is where
I would start. See the references below.
1. Lankford SM, Bai SA, Goldstein JA. Cloning of canine cytochrome
P450 2E1 cDNA: identification and characterization of two variant
alleles. Drug Metab Disp 2000;28:981-986.
2. Paulson SK, Engel L, Reitz B, et al. Evidence for polymorphism
in the canine metabolism of the cyclooxygenase 2 inhibitor, celecoxib.
Drug Metab Disp 1999;27:1133-1142.
3. Sagara K, Mizuta H, Ohshiko M, et al. Relationship between the
phasic period of interdigestive migrating contraction and the systemic
bioavailability of acetaminophen in dogs. Pharm Res 1995;12:594-598.
8. Paulson SK, Vaughn, MB, Jessen SM, et al. Pharmacokinetics of
celecoxib after oral administration in dogs and humans: effect of food
and site of absorption. J Pharmacol Exp Therap 2001;297:638-645.
9. Paulson SK, Zhang JY, Jessen SM, et al. Comparison of celecoxib
metabolism and excretion in mouse, rabbit, dog, cynomolgus monkey and
rhesus monkey. Xenobiotica, 2000;30:731-744.
10. Court MH, Hay-Kraus BL, Hill DW, et al. Propofol hydroxylation
by dog liver microsomes: assay development and dog breed differences.
Drug Metab Disp 1999;27:1293-1299.
11. Dalvi RR, Nunn VA, Juskevich J. Hepatic cytochrome P-450
dependent drug metabolizing activity in rats, rabbits and several food
producing species. J vet Pharmacol Therap 1987;10:164-168.
12. Lewis DFV, Lake BG. Species differences in coumarin metabolism:
a molecular modeling evaluation of CYP2A interactions. Xenobiotica
13. Kararli TT. Gastrointestinal absorption of drugs. CRC Crit Rev
Therap Drug Carr Sys 1989;6:39-86.
14. Sallovitz J, Lifschitz A, Imperiale F, et al. Breed differences
on the plasma availability of moxidectin administered pour-on to calves.
Vet J 2002;164:47-53.
Rob Hunter, MS, PhD
Assistant Professor of Veterinary Pharmacology
Zoological & Analytical Pharmacology Laboratory
Department of Anatomy & Physiology
129 Coles Hall
College of Veterinary Medicine
Kansas State University
Manhattan, Kansas 66506-5802
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In such a situation we need to consider all the possibilities right
Is the formulation same
Where was the iv bolus injected
Breed of the dog (some time cross breeds may be used)
Type of feed
Sampling time points and sampling port
Assay procedure and validation
Lower limit of quantitation of the assay
Calculation method (Software used if any)
Time points used to calculate the elimination rate.
All we can do is eliminate these possibilities and any others, if exist.
Each minute detail may be important.
Hope this helps,
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It seems that you have received a good deal of possible explanations on
why you observe the different half-lives. However, I have a couple of
question for you. first, how many dogs were included in each center?
Second, and this might sound somewhat trivial, are there any dogs with
extra-ordinary half-life values in your study? Whenever I am presented
with only a mean value of something, I take a closer look at the data
to make sure that the mean is not skewed by 1 or 2 individual values.
Surprisingly, this is rather usual than exception and many times there
are some outliers that have impact on the mean value of the whole
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