Pet Forum / Miscellaneous / Animal Health / February 2008

Got the following from a friend of mine in my e-mail (who got it off another
discussion board). Thought I'd repost it here. (hope the original authors
have no objection)

Dale

<< I'd like to throw in an NSAID for possible chemoprevention, but have some
worries about the liver due to the phenobarb >>

Normally, phenobarbital (PB) increases elimination of xenobiotics
(drugs with toxic metabolites) via the cytochrome P 450 pathway.
However, there is evidence that many NSAIDS increase liver toxicity

when used with PB. Some may be used that appear to have less toxic
potential. In veterinary medicine...perhaps the newer coxibs fit that
criteria however, they are not all the same as well.

Reasons:
Phenobarbital induces the metabolism of drugs (Cytochrome P-450 pathway)that
are substrates of CYP2C, CYP2D, and CYP3A; however, Phenobarbital is
eliminated predominantly by CYP2C9-and CYP2C19-dependent hepatic metabolism.
Many NSAIDS are extensively metabolized by CYP2C19 and could potentially
influence phenobarbital elimination by acting as an alternate substrate for
this isoenzyme. Hence some NSAIDs may combine with PB to induce
hepatotoxicity. Some NSAIDS ie sulindac, naproxen, ketoprofen, diclofenac,
rofecoxib, and etoricoxib have little effect on CYP2 metabolism and may be

less toxic when used with PB. Others like: ibuprofen, indomethacin,
flurbiprofen, celecoxib, valdecoxib, lornoxicam, tenoxicam, meloxicam, and
piroxicam have more of an impact and expect to be more toxic.

In addition...the use of high dose fish oils seems to
down-regulate cytochrome P-450 gene expression.

Hence, one can see a benefit of such usage.

Lester Mandelker DABVP, FAAVPT

" Impact of CYP2C9 genotype on pharmacokinetics: are all

cyclooxygenase inhibitors the same? "

Rodrigues AD.

Drug Metabolosm, Bristol-Myers Squibb, Princeton, NJ 08543, USA.
david.rodrigues@bms.com

The market withdrawals of rofecoxib (Vioxx) and valdecoxib (Bextra) have
focused considerable attention on the side effect profiles of cyclooxygenase
(COX) inhibitors. As a result, attempts will be made to identify risk
factors in the hope that physicians might be able to ensure patient safety.
At first glance, CYP2C9 genotype might be considered a risk factor because
many COX inhibitors are CYP2C9 substrates in vitro. This observation has led
some to hypothesize that a reduction in clearance, in subjects expressing
variant forms of the enzyme (e.g., CYP2C9*1/*3 or CYP2C9*3/*3 genotype),
will lead to increased exposure and a greater risk of cardiovascular or
gastrointestinal side effects. For any drug, however, one has to consider
all clearance pathways. Therefore, a number of COX inhibitors were surveyed
and it was determined that CYP2C9 plays a relatively minor role in the
overall clearance (<or=20% of the dose) of sulindac, naproxen, ketoprofen,
diclofenac, rofecoxib, and etoricoxib. CYP2C9 genotype would have no
clinically meaningful impact on the pharmacokinetics of these drugs. In
contrast, CYP2C9 genotype is expected to impact the clearance of ibuprofen,
indomethacin, flurbiprofen, celecoxib, valdecoxib, lornoxicam, tenoxicam,
meloxicam, and piroxicam. However, even when CYP2C9 is a major determinant
of clearance, it is necessary to consider CYP2C8 genotype (e.g., ibuprofen)
and, possibly, CYP3A4 activity (e.g., celecoxib, valdecoxib, and meloxicam)
also.

" N-6 and n-3 polyunsaturated fatty acids down-regulate cytochrome
P-450 2B1 gene expression induced by phenobarbital in primary rat
hepatocytes. "
Li CC, Lii CK, Liu KL, Yang JJ, Chen HW.

Department of Nutrition, Chung Shan Medical University, Taichung 402,
Taiwan.

In mammals, polyunsaturated fatty acids (PUFAs) act not only as an important
energy source, but also as substrates for cellular membrane and hormone
formation. They also play key roles in cellular metabolism and gene
regulation. The objective of the present study was to determine whether
individual n-6 and n-3 PUFAs affect cytochrome P-450 2B1 (CYP 2B1)
expression induced by phenobarbital (PB) in primary rat hepatocytes. We used
100-microM arachidonic acid (AA), linoleic acid, eicosapentaenoic acid and
docosahexaenoic acid (DHA) to test this hypothesis. Phenobarbital-induced
CYP 2B1 expression was down-regulated by n-6 and n-3 PUFAs, especially AA
and DHA. Prostaglandin (PG) E2 but not PGE3 was found to down-regulate
PB-induced CYP 2B1 expression. The cyclooxygenase inhibitor indomethacin (20
microM) attenuated the down-regulation of CYP 2B1 gene expression by n-6 and
n-3 PUFAs induced by PB, and maximal attenuation was found in the AA-treated
group. We also studied the PGE2 downstream cyclic adenosine monophosphate
(cAMP)-dependent protein kinase A (PKA) pathway to determine its role in the
down-regulation of CYP 2B1 expression by AA with the use of 0.4 mM of the
adenylate cyclase inhibitor 9-(tetrahydro-2'-furyl)adenine] (SQ22536) and
7.5 microM of the PKA inhibitor H-89. Both inhibitors attenuated the
down-regulation of CYP 2B1 expression by AA. These results suggest that
PB-induced CYP 2B1 expression is down-regulated by n-6 and n-3 PUFAs through
different pathways. Prostaglandin E2 and the cAMP-dependent PKA pathway were
involved in AA down-regulation of CYP 2B1 expression, whereas the
down-regulation by n-3 PUFAs is not fully understood yet and the
glucocorticoid receptor/constitutive androstane receptor/retinoid X receptor
signal transduction cascade can be involved.