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Re: AUC, grapefruit }} Squiggles

Posted by sdb on July 8, 2006, at 19:47:08

In reply to Re: Rumination-snapper }} Squiggles sdb, posted by Squiggles on July 8, 2006, at 19:15:21

> > Here is a study but diazepam is not only metabolized by CYP3A4:
> > ------------------------------------------------------------------

> >
> > Eur J Drug Metab Pharmacokinet. 1998 Jan-Mar;23(1):55-9. Related Articles, Links
> >
> > Interaction between grapefruit juice and diazepam in humans.
> >
> > Ozdemir M, Aktan Y, Boydag BS, Cingi MI, Musmul A.
> >
> > Department of Pharmacology, Medical Faculty, University of Osmangazi, Eskisehir, Turkey.
> >
> > Grapefruit juice has been reported to markedly improve the bioavailability of triazolam, midazolam, terfenadine, cyclosporine and several dihydropyridine calcium channel blockers including felodipine, nifedipine, nitrendipine and nisoldipine. Because these drugs are metabolized by the hepatic cytochrome P450 isozyme (CYP) 3A4, the inhibitory effect of grapefruit juice is thought to results from inhibition of CYP3A4. In this study, our aim was to investigate the effects of grapefruit juice on plasma concentrations of diazepam. Eight healthy male and female subjects participated in this study. Oral (5 mg) diazepam was administered with either 250 ml water and grapefruit juice. Blood samples were collected for a 24 h period, and whole blood concentrations of diazepam were measured enzyme immunoassay. The mean AUC(0-24) of diazepam was increased 3.2-fold (P < 0.001) and Cmax was increased 1.5-fold (P < 0.05) by the grapefruit juice. Grapefruit juice postponed the tmax of diazepam from 1.50 h to 2.06 h (P < 0.01).
> >
> Interesting; drug interactions are interesting in
> general but to know exactly what effect one
> drug has on another, or on an enzyme or hormone
> can be very useful. In this case the inhibition of grapefruit juice (not just grapefruit because
> of quantity i would imagine) can be used for or
> against the potentiation of these drugs. I use
> the word potentiation but that may not be quite
> correct. What is bioavailability? Does it mean that the blockage of cytochrome P450 isozyme represses the liver metabolism, and therefore the
> stuff is voided, much like lithium's kidney voidance is increased by sodium and potassium?
> Also, how would you use this cytochrome blockage to the advantage of regulating the benzo dose?
> It might take some fine measurement.
> Squiggles

Bioavailability is a measurement of "how much" from the therapeutically active substances reach
the systemic circulation and later the site of action eg. for diazepam: the brain -> if you take grapefruit juice more active diazepam will reach your brain because of a "modified" first pass in the liver. Substances will spread out in to different compartiments. Diazepam should reach the brain to have the drugs clinical response.

If you give something IV the bioavailability is 100%. If you take a drug orally you will not reach
100%, because of poor absorption from the gastrointestinal tract, degradation or metabolism of the drug prior to absorption, hepatic first pass effect, lipid membranes etc.

There is more to tell about but bioavailability (AUC = Area under the curve) means the amount of substance that really reaches for example the receptors of brain GABA-CL channels in the case of diazepam, clonazepam.





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