Back to the Top
sir,i am working on a drug on which no absorption data is available.i
want to find out whether its transport is carrier mediated or not.how
can i do it experimentally?
and how is it possible that a drug is rapidly absorbed,has a tmax. of
3 hrs. orally,is very water soluble,has a low molecalar weight and
still has a very low bioavailability(30-35%).
thanking you in anticipation of a reply.
warm regards
shweta
Back to the Top
The following message was posted to: PharmPK
Shweta,
You need to check up its presystemic elimination. I
would not say that a drug with Tmax of 3 hours "is
rapidly absorbed". Please, give a definition for
specifying a drug as rapidly absorbed.
What do you mean with "bioavailability?" Is it
absolute bioavailability or it is relative
bioavailability?
Kind Regards,
D. Terziivanov
Dimiter Terziivanov, MD,PhD,DSc, Professor
Head, Clinic for Clinical Pharmacology and
Pharmacokinetics,
Univ Hosp "St. I.Rilsky",
15 Acad. I. Geshov st, 1431 Sofia, Bulgaria
Tel:(+ 359 2)8510639;(+ 359 2)5812 828.
Fax:(+ 359 2)8519309. e-mal: terziiv.aaa.yahoo.com
Back to the Top
The following message was posted to: PharmPK
Dear Shweta,
As regards to your question about the bioavailability being low, we
might have a situation where the drug is being extensively metabolized
by the liver or even the intestinal wall. The systemic bio
availability, as we define it, is the product of three components, the
fraction of the drug in the lumen that is absorbed ( fa), the fraction
of the drug that gets across the intestinal wall intact (fg) and
finally the fraction that escapes metabolism by the liver (fh). Thus, F
= fa * fg * fh.
Thus is case of the drug in question it seems that fa is high (since
you say it is rapidly absorbed and water soluble) but it seems likely
that it is extensively metabolized before it reaches the systemic
circulation (the blood) which is our site of measurement.
Thank you,
Naveed
Back to the Top
Shweta Agarwal asked:
"sir,i am working on a drug on which no absorption data is available.i
want to find out whether its transport is carrier mediated or not.how
can i do it experimentally?
and how is it possible that a drug is rapidly absorbed,has a tmax. of
3 hrs. orally,is very water soluble,has a low molecalar weight and
still has a very low bioavailability(30-35%)."
First we need to know the measured and estimated permeability of the
drug. Take for example a small hydrophilic drug like Gabapentin (log P
= -2.59). This drug is predicted (from in silico estimation of human
Peff) to have very low passive transcellular permeability. However, by
virtue of the size and amino acid functional group it is a substrate
for the amino acid transporters in the upper part of the small
intestine and has Tmax = 3 hours. A dose of 400 mg is absorbed ~55% and
a dose of 1600 mg is absorbed only 32%. Clearly the non-linear dose
dependence is due to saturation of the transporter since all of the
absorbed Gabapentin is excreted unchanged in the urine (T1/2 ~ 3 hr.)
and requires tid dosing.
Using in vitro Km values derived from inhibition of 14C-phenylalanine
uptake by LAT1, GastroPlus simulates the non-linear dose dependence
exactly and predicts that a dose of 40 mg would be 95% absorbed. In
addition, we can test the effect of various methods of delivery. We
predict that a gastric retentive delivery device with slow release of
400 mg would have higher bioavailability, allow for once per day
dosing, and result in less fluctuation of peaks and troughs. This makes
sense if the simulation takes into consideration the physiological
distribution of the amino acid transporter. Expression of these influx
transporters is highest in the duodenum and jejunum. Thus in effect, a
gastric retentive device will slowly release the drug into a capacity
limited funnel in the upper GI resulting in improved performance.
Mike
PharmPK Discussion List Archive Index page
Copyright 1995-2010 David W. A. Bourne (david@boomer.org)