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I've been using microsomes to calculate clearance values and using
physiological parameters cited in the literature. For human I've used
45 mg microsomes / g liver and 20 g liver / kg body weight from Obach
(Obach, 1999). Colleagues in the same lab as me have been using 25.7 g
liver / kg body weight (Davies and Morris, 1993). Which is the better
reference? The value of 45 mg microsomes / g liver is cited as Houston
(Houston, 1994). Houston in turn cites four other papers, three of which
are rat and one which is rat, dog and human, where values of 54, 43 and
77 mg microsomal protein / g liver are given for rat, dog and man
respectively (Baarnhielm et al, 1986).
My aim is to calculate intrinsic and hepatic clearances of NCEs in
human, rat and mouse using liver microsomes and cyropreserved
hepatocytes. I fear that I'm going to get bogged down with formulae
which require a knowledge of physiological parameters, about which there
is contradictory information (or is it just that there is a lot of
variability in these parameters?). Does anyone have any suggestions as
to where to obtain physiological parameters that I can use in my
calculations with confidence?
Thanks in advance,
Seetal
References:
Obach RS. Prediction of human clearance of twenty-nine drugs from
hepatic microsomal intrinsic clearance data: An examination of in vitro
half-life approach and non-specific binding to microsomes. Drug
Metabolism and Disposition, (1999) 27(11): 1350-1359
Davies B and Morris T. Physiological parameters in laboratory animals
and humans. Pharmaceutical Research (1993) 10(7): 1093-1095
Houston BJ. Utility of in-vitro drug metabolism data in predicting
in-vivo metabolic clearance. Biochemical Pharmacology (1994) 47(9):
1469-1479
Baarnhielm C, Dahlback H and Skanberg I. In-vivo pharmacokinetics of
felodipine predicted from in-vitro studies in rat, dog and man. Acta
Pharmacol. et toxicol. (1986) 59: 113-122
Dr Seetal Dodd
Research Fellow
Department of Pharmaceutics,
Victorian College of Pharmacy, Monash University
381 Royal Parade, Parkville, Victoria 3052
Australia.
Tel: +61 3 9903 9053
Fax: +61 3 9903 9583
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The following message was posted to: PharmPK
Report of the Task Group on Reference Man (international commission on
radiological protection report no.23)
Pergamon Press 1975
Reference Man has a body weight of 70 kg and liver weight of 1800g, hence
1800/70= 25.7 g/kg
Reference Woman has a bodyweight of 58 kg and liver weight of 1400g, hence
1400/58 = 24.1 g/kg
rgds,
Armel Stockis
UCB Pharma Sector
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The following message was posted to: PharmPK
Seetal Dodd(by way of David_Bourne) wrote:
>
>I've been using microsomes to calculate clearance values and using
>physiological parameters cited in the literature. For human I've used
>45 mg microsomes / g liver and 20 g liver / kg body weight...>>
Dear Seetal:
1) Instead of microsomal weight (wet or otherwise), it is better to
use microsomal protein content: 20.8 mg microsomal protein/g human
liver +_5.04 (Standard deviation) - for reference see:
Lipscomb, J.C., C.M. Garrett, and J.E. Snawder. 1997. Cytochrome P450
dependent metabolism of trichloroethylene: Interindividual
differences in humans. Toxicol. Appl. Pharmacol. 142: 311-318.
Lipscomb, J.C., J.W. Fisher, P.D. Confer, and J.Z. Byczkowski. 1998.
In vitro to in vivo extrapolation for trichloroethylene metabolism in
humans. Toxicol. Appl. Pharmacol. 152: 376-387.
2) In humans the median liver weight i'm males and females aged 20-29
is 1820 and 1440 g, respectively, or about 2.6% of the body weight.
The liver weight, which is relatively unchanged throughout the
adulthood, is reduced by about 25% over the age of 65 years when
compared to 40 years - for reference see:
Brown R.P. et al. 1997. Physiological parameter values for
physiologically based pharmacokinetic models. Toxicol. Industrial
Health 13:407-484.
Best wishes.
Janusz Z. Byczkowski, Ph.D.,D.Sc.,D.A.B.T.
Consultant
212 N. Central Ave.
Fairborn, OH 45324
voice (937)878-5531
office (614)644-3070
FAX (208)330-9302
e-mail januszb.aaa.AOL.com
homepage: http://members.aol.com/JanuszB/index.html
JZB Consulting web site: http://members.delphi.com/januszb/
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