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kaushal joshi

on 17 September 2012

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Transcript of hi2

Assessment of Intestinal Availability of Various Drugs
in Oral Absorption Process Using Portal Vein Cannulated Rats Yoshiki Matsuda a, Yoshihiro Konno, Masahiro Satsukawa, Taro Kobayashi, Yu Takimoto, Kunihiko Morisaki and Shinji Yamashita DMD Fast Forward. Published on September 4, 2012 as doi:10.1124/dmd.112.048223 Brought to you by: Kaushal Joshi Abstract In order to understand the rate-limiting process of oral drug absorption, not only total bioavailability (F) but also intestinal (Fa·Fg) and hepatic (Fh) availability after oral administration should be evaluated Usually, Fa·Fg of drug is calculated from pharmacokinetic parameters after intravenous and oral administration In this study, portal vein cannulated rats were used to calculate the Fa·Fg of drugs from a single oral dosing experiment without data from
intravenous injection. new operative method that enables stable portal vein blood flow Simulation of portal and systemic plasma concentrations by PBPK indicated that the balance of the ka and ke resulted in different patterns in portal and systemic plasma concentration-time profiles provide a new experimental animal model

that enables identification of the factors that limit oral bioavailability


to provide pharmacokinetic information on the oral absorption Body Body Body Body Body Body This approach is influenced markedly by the estimated value of Fh, which varies with the hepatic blood flow used in the calculations surgery had no effects on hepatic blood flow and metabolic activity

Fa·Fg was validated Introduction Innovation
high affinity and selectivity ... small high molecular weight
high lipophilicity
low solubility Poor % F due to:
Transporter efflux
Low solubility
Low Permeablity F = Fa Fg Fh Fl Typically, Fa·Fg = F / Fh,
BUT,,,, IV and PO are required Portal vein cannulation allows...
unrestrained sampling of systemic and portal blood simultaneously
without the necessity of anesthesia Canuumation was improved to obtain stable blood flow in the portal vein,
Fa·Fg in the portal vein cannulated rats was assessed after oral
administration of indomethacin, midazolam, felodipine,
fexofenadine, raloxifene, sulpyride and famotidine PBPK (cc) image by rocketboom on Flickr (cc) image by quoimedia on Flickr Fa·Fg is evaluated by measuring the difference between portal and systemic blood concentrations after oral dosing RESULT Discussion Fh = 1 - CLh / Qh Fa·Fg = F / Fh fdghfdh Fa·Fg and Fh calculated by eq. are significantly affected by the hepatic blood flow used for the calculations.

When hepatic blood flow changes only 1.3-fold (60 to 80 mL/min/kg), Fa·Fg shifts from 0.43 to 1.15 (2.7-fold).

This means that inter-individual differences in hepatic blood flow used for intravenous and oral administration studies may result in the inaccurate
estimation of oral absorbability Fa·Fg = Qpor · Rb · (AUCpor - AUCsys) / Dose Fa·Fg was relatively stable, changing only 1.3-fold when the portal
blood flow changed 1.3-fold (30 to 40 mL/min/kg).

An additional advantage of our method is that Fa·Fg can be calculated from a single oral dosing; intravenous administration studies and estimation of non-hepatic clearance are not required

Typical cannulating method from iliac vein to the portal vein alter the blood flow. While in this method of portal cannulation doesn't affect hepatic blood flow as calculated from clearance of lidocain (Table 3) ...Conclusion... Novel method describes...

Assessment of intestinal availability under similar physiological conditions to untreated rats

PK properties of drugs relating to oral absorption and systemic elimination rate constant

Highly advantageous in identifying factors that limit oral F when considering development of oral candidate Surgical procedure A simple idea that generates enthusiasm will go further than a great idea that inspires no one (Mary Kay Ash). So don’t look at things that are and ask “Why?”. Instead, dream of things that never were and say – “Why not?” (George Bernard Shaw). Do not discourage yourself - it’s difficult to tell what’s impossible, for the dreams of yesterday are the hope of today and can easily turn in the reality of tomorrow (Unknown). Don't dream at night - dream all day! Dream for a living (Steven Spielberg).
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