Re: JAMA on FDA & PHARMA: Lack of vigilance, lack of trust

From: Steve Harris sbharris_at_ROMAN9.netcom.com (sbharris_at_ix.netcom.com)
Date: 11/30/04 

Date: 30 Nov 2004 14:56:51 -0800

"beachhouse" <sendnomail@please.com> wrote in message news:<cofb5f$1c10
> Have you seen the idiotic way the combination simvastatin/ezitimibe product
> t is being marketed to patients on T.V.?
> "it works on *both* kind of cholesterol.... you get cholesterol from your
> parents and from your food..."
> implication being that you need 2 drugs by necessity to achieve meaningful
> lipid lowering.
> what crap.

COMMENT:

Yes, the another ironic twist added inasmuch as probably THE main
mechanism of ezetimibe/Zetia cholesterol lowering is much like that of
bile acid binders: it prevents reabsorption of your own *hepatically
excreted* biliary cholesterol, too, as well as the cholesterol you
eat. Which means it also (and probably mainly) affects the cholesterol
you make, a.k.a. the cholesterol you "get from your
parents'[cholesterol control genes]".

The effect of Zetia is just too large to be affecting only the
cholesterol you absorb from your diet. I WISH you could lower LDL 25%
in anybody by merely removing most of the cholesterol from their diet.
But you can't, unless you really cut their calories and saturated fat
intake, too.

Zetia would presumably work reasonably well even in vegans (who by
definition eat no dietary cholesterol), though I can't find that this
interesting experiment has ever been tried.

That said, I agree that the jury's out on whether or not Zetia's or
Zetia combos are going to do anything clinically, anymore than bile
acid binding resins like cholestyramine/Questran did.

Note that the abstract below says it's not known how ezetimibe works,
but it's been recently found to bind to the aminopepdidase N (CD13)
receptor. That's an important viral endocytosis receptor. Maybe the
stuff will end up as a useful antiviral adjunct therapy, if it doesn't
help heart disease.

SBH

Can J Clin Pharmacol. 2003 Winter;10 Suppl A:13A-20A.

The pharmacokinetics of ezetimibe.

Simard C, Turgeon J.

Universite de Montreal, Quebec.

Ezetimibe is the first member of a new class of selective cholesterol
absorption inhibitors. The drug and its active glucuronide metabolite
impair the intestinal reabsorption of both dietary and hepatically
excreted biliary cholesterol through inhibition of a membrane
transporter yet to be identified. Absorption of ezetimibe is rapid and
not altered by food content following oral
administration. The drug is not metabolized by the cytochrome P450
system but
extensive glucuronidation takes place in the intestine. Consequently,
plasma
concentrations of ezetimibe represent approximately 10% of total
ezetimibe in
plasma. Enterohepatic recirculation observed for ezetimibe and its
glucuronimide significantly increases the residence time of these
compounds in the intestine, at their site of action. Elimination of
ezetimibe glucuronimide appears impaired in elderly patients and
patients with renal insufficiency with plasma concentrations increased
1.5- to 2-fold. So far, no drug interaction study has been associated
with major changes in either the pharmokinetics of ezetimibe or
coadministered drugs.

Publication Types:
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PMID: 14571304 [PubMed - indexed for MEDLINE]

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