- On 1 Apr 2004 at 15:19:54, "Harold Boxenbaum" (harold.at.arishel.com) sent the message
Don't know about Evans Blue, but here are a lot of "goodies" about

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blood volume, etc. Enjoy! Harold

Species\0xED Body Masses (kg), Gut Volumes (mL) & Maximum Drug Solubility

in Species\0xED Guts. Gut Mass and Volume Data from Davies & Morris,

1993:

Species Mass Gut Mass

Mouse 0.02 kg 1.5 mL

Rat: 0.25 kg 11.3 mL

Rabbit: 2.5 kg 120 mL

Monkey: 5 kg 125 mL

Dog: 10 kg 215 mL

Human: 70 kg 1100 mL

Jennifer Dressman has suggested (personal communication) that a

'rule-of-thumb' to evaluate whether or not a dose of drug will

completely dissolve in the human gut, is to take the dose and determine

if it is capable of dissolving in 500 mL water. Five hundred mL water

is 45.5 % of the human gut volume, so we might apply this percentage to

other species. In doing so, we obtain the following for other species:

Mouse 0.68 mL

Rat 5.1 mL

Rabbit 55 mL

Monkey 57 mL

Dog 98 mL

Human 500 mL

For example, is a drug has a water solubility of 1 mg/mL, and we

administer more than 5.1 mg to a rat, we will likely have undissolved

drug passing through the GUT. In this case, look for 'flip-flop'

pharmacokinetics.

Interspecies Body Surface Area

Many laboratory scientists utilize Appendix II in the publication by

Freireich et al (1966) to calculate species body surface area (BSA).

Unfortunately, the data upon which this approach is based is

considerably unreliable. Therefore, it is recommended you do not use

this method. Rather, body surface area in all terrestrial mammals may

be accurately estimated by utilizing the simple allometric equation

(Calder, 1984; Boxenbaum & D\0xEDSouza, 1990; Stahl, 1967) :

BSA (m^2) = 0.1110 B (kg) ^ 0.65

A 3 gram shrew has a BSA of 0.848 m2/kg, compared to 0.0251 m2/kg for a

human. Based on body mass, the shrew has 34 times the surface area of

the human. Consequently, a shrew requires much more food intake per kg

body mass to compensate for radiant heat loss across its significantly

larger, relative body surface area. An animal deprived of food for 2-3

hours could easily die (Burton and Burton, 1975).

For possibly the best discussion of body surface surface area, as well

other variables for interspecies biological extrapolation, see Chappell

and Mordenti (1991).

Human Body Surface Area

In 1916, Du Bois & Du Bois published an equation for calculation of

body surface area (BSA) in humans, based on a sample size of 9

individuals. That equation is (appropriately adjusted for units):

BSA (m^2) = 0.007184 x [(Height, cm) ^ 0.725] x (Body

Mass, kg) ^ 0.425

Using a much larger sample size, Gehan and George (1970) obtained the

following analogous equation:

BSA (m^2) = 0.02350 x [(Height, cm) ^ 0.42246] x

[(Body Mass, kg) ^ 0.51456]

Although the equation of Du Bois & Du Bois is frequently used in

clinical trials for calculation of BSA, it is less accurate than the

equation of Gehan and George. Nonetheless, scientists sometimes

continue to use the Du Bois & Du Bois equation for the sake of

consistency between previous studies which previously employed the

DuBois n DuBois equation.

Terrestrial Mammals\0xED Hematocrit & Blood and Plasma Volume

(Prothero, 1980)

Blood volume (mL) = 0.086 (B, grams) ^ 0.99 or about 8.6 % of body

mass

Red blood cell volume (mL) = 0.036 (B, grams) ^ 0.97

Dividing the equation for RBC volume by blood volume, one obtains

hematocrit. Hematocrit (H) therefore equals H = 0.4186 (B, grams)

-0.02 or about 0.4 for all terrestrial mammals

Plasma volume = blood volume x (1- hematocrit), or about 5.2 % of

body mass

Human Hepatic Blood Flow (QH)

Greenway & Stark (1971) surveyed the literature and determined the best

value for human hepatic blood flow to be 104 mL/min per 100 grams of

liver mass. Taking the human male liver mass to be 1800 grams (Snyder,

chair, Report of the Task Group on Reference Man, 1975), one obtains

the following for male, human hepatic blood flow:

(104 mL/min per 100 grams liver mass) x (1800 grams) = 1872

mL/min

Taking the male body mass to be 70 kg, QH (human male) = (1872

mL/min)/(70 kg)

26.7 mL/min/kg.

For the female, the average liver mass = 1400 grams in an average 58 kg

body. QH (human female) = (104 mL/min per 100 grams liver mass)

x (1400 grams) / (58 kg body mass)

= 25.1 mL/min/kg. A generalized value might therefore be about 25

mL/min/kg

Lean Body Mass (LBM) Calculation

Lean body mass equals total body mass minus fat mass.

Without going into its history, which involves a very hard-to-get

reference with vagaries, typographical errors, etc., one may reliably

calculate lean body mass (total body mass minus fat mass) from the

following two equations (Morgan & Bray, 1994: there were typographical

errors in equation 1 of this reference which were corrected in the

equations listed below)

LBM (men) = [1.10 B ] n [ 128 (B/Ht)^2 ]

LBM (women)= [1.07 B ] n [ 148 (B/Ht)^2 ]

where B is body mass in kg, and Ht is height in cm.

For a 70 kg male having a height of 166 cm,

LBM = [1.10 x 70 ] n [ 128 (70/166)^2 ] = 77.00 n 22.76 = 54.24

kg

Body Mass Index

From: http://www.niddk.nih.gov/health/nutrit/pubs/statobes.htm#what

'A number of methods are used to determine if someone is overweight or

obese. Some are based on the relation between height and weight; others

are based on measurements of body fat. The most commonly used method

today is body mass index (BMI).

BMI can be used to screen for both overweight and obesity in adults. It

is the measurement of choice for many obesity researchers and other

health professionals, as well as the definition used in most published

information on overweight and obesity. BMI is a calculation based on

height and weight, and it is not gender-specific. BMI does not directly

measure percent of body fat, but it is a more accurate indicator of

overweight and obesity than relying on weight alone.

BMI is found by dividing a person\0xEDs weight in kilograms by height in

meters squared. The mathematical formula is:

BMI = Weight (kg) / Height Squared (m^2)

To determine BMI using pounds and inches, multiply your weight in

pounds by 704.5,* then divide the result by your height in inches, and

divide that result by your height in inches a second time. (Or you can

use the BMI calculator at http://www.nhlbisupport.com/bmi/ or check the

chart shown below that has calculated BMI for you.)'

Underweight: Below 18.5

Normal: 18.5 n 24.9

Overweight: 25.0 n 29.9

Obesity: 30.0 and Above (e.g., B=101

kg, Ht = 165 cm; BMI = 37.1)

Harold Boxenbaum, Ph.D.

Pharmaceutical Consultant

Arishel Inc.

14621 Settlers Landing Way

North Potomac, MD 20878-4305

(P) 301-424-2806

(F) 301-424-8563

Email: harold.-a-.arishel.com

Website: www.arishel.com - On 1 Apr 2004 at 18:50:35, "Clerk Maxwell" (clerkmaxwell.at.hotmail.com) sent the message

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Here are the missing references, plus some extra I did not have time to

cull out. Harold

Bonate PL, Howard D, Prospective allometric scaling: does the emperor

have cloths? J Clin Pharmacol 40:335-340 (2000)

Bonate PL, Howard H, Rebuttal to Mahmood, J Clin Pharmacol 40:345-346

(2000)

Boxenbaum H, Interspecies variation liver weight, hepatic blood flow,

and antipyrine intrinsic clearance: Extrapolation of data to

benzodiazepines and phenytoin. J. Pharmacokin. Biopharm. 8:165-176

(1980).

Boxenbaum, H, Interspecies scaling, allometry, physiological time, and

the ground plan of pharmacokinetics. J. Pharmacokin. Biopharm.

10:201-227 (1982).

Boxenbaum H, 'Interspecies pharmacokinetic scaling: Desultory

reflections,' In: 'Pharmacokinetic / Pharmacodynamic Analysis:

Accelerating Drug Discovery and Development,' Schlegel (ed), Biomedical

Library Series, International Business Communications, Inc,

Southborough, MA, 1996, Chapter 2.6, pp 2.6.1 n 2.6.18.

Boxenbaum H, DiLea C, First-time-in-human dose selection: Allometric

thoughts and perspectives, J Clin Pharmacol 35:957-966(1995).

Boxenbaum, H. & D\0xEDSouza, R.W, Interspecies pharmacokinetic scaling,

biological design and neoteny. Advances in Drug Research (B. Testa,

ed.) 19:139-196 (1990).

Burton M & Burton R, 'Encyclopedia of Mammals,' Octopus Books, London,

1975.

Calder III WA. 'Size, Function, and Life History,' Harvard Univ Press,

Cambridge, MA, 1984.

Cephalopoda Cuvier, 1797:

http://tolweb.org/tree?group=Cephalopoda&contgroup=Mollusca

Chiou W et al, Correlation of plasma clearance of 54 extensively

metabolized drugs between humans and rats: Mean allometric coefficient

of 0.66. Pharm Res 15:1474-1479 (1998).

Davies B, Morris T, Physiological parameters in laboratory animals and

humans. Pharmaceutical Research 10:1093-1095

Du Bois D & Du Bois EF, A formula to estimate the approximate surface

area if height and weight be known, Arch Int Med 17:683-871,1916.

Edwards NA. Scaling of renal functions in mammals. Comp Biochem Physiol

52A 63-66, 1975.

Feng are et al, Allometric pharmacokinetic scaling: Towards the

prediction of human oral pharmacokinetics, Pharm Res 17:410-418 (2000).

Gehan EA & George SL, Estimation of human body surface area from height

and weight, Cancer Chemother Reports, Part I, 54:225 n 235, 1970.

Gould SJ, Allometry and size in ontogeny and phylogency, Biol Rev

41:587-640(1966)

Gould SJ, One standard lifespan. New Scientist 81:388-289(1979).

Greenway CV, Stark RD. Hepatic vascular bed. Physiol Rev 51:23-65,1971

Gunther B, de la Barra L, On the space-time continuum in biology, Acta

Physiol Latinamerica 16:221-231(1966).

Lave T et al, The use of human hepatocytes to select compounds based on

their expected hepatic extraction ratios in humans, Pharm Res

14:152-155(1997).

Lave T et al, Prediction of hepatic metabolic clearance based on

interspecies allometric scaling techniques and in vitro-in vivo

correlations, Clin Pharmacokin 36:211-231(1999).

Mahmood I, Interspecies scaling: Role of protein binding in the

prediction of clearance from animals to human, J Clin Pharmacol

40:1439-1446(2000).

Mahmood I, Critique of prospective allometric scaling: Does the emperor

have cloths? J Clin Pharmacol 40:341-344(2000).

Mahmood I, Balian JD, Interspecies scaling: Predicting pharmacokinetic

parameters of antiepileptic drugs in humans from animals with special

emphasis on clearance, J Pharm Sci 85:411-414(1996).

Mahmood I, Balian JD, Interspecies scaling: predicting clearance of

drugs in humans. Three different approaches. Xenobiotica

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McMahon, T. A. & Bonner, J. T. 'On Size and Life,' Scientific American

Books, NY, 1983.

Mordenti J. Man versus beast: Pharmacokinetic scaling in mammals. J

Pharm Sci 75:1028-1040,1986.

Mordenti J, Chen SA, Moore JA, Ferraiolo BL, Green JD. Interspecies

scaling of clearance and volume of distribution for five therapeutic

proteins. Pharm Research 8:1351-1359, 1991.

Morgan DJ & Bray KM. Lean body mass as a predictor of drug dosage:

Implications for drug therapy. Clin Pharmacokin 26:292-307,1994.

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 nonspecific binding to microsomes, Drug Metab

Dis 27:1350-1359(1999).

Obach RS et al, The prediction of human pharmacokinetic parameters from

preclinical and in vitro metabolism data, J Pharmacol Exp Therap

283:46-58(1997).

Prothero JW. Organ scaling in mammals: The liver. Comp Biochem Physiol

71A:567-577,1982.

Prothero JW. Scaling of bodily proportions in adult terrestrial

mammals. Am J Physiol 262: R492-R503,1992.

Prothero JW. Scaling of blood parameters in mammals. Comp Biochem

Physiol 67A 649-657,1980.

Report of the Task Group on Reference Man, see Snyder WS

Sacher GA, Relationship of lifespan to brain weight and body weight in

mammals, Ciba Found. Colloq. Aging 5:115-133(1959)

Schmidt-Nielsen, K. 'Scaling: Why is Animal Size so Important?'

Cambridge University Press, Cambridge, England, 1984.

Shibata Y, Takahashi H, Ishii Y, A convenient in vitro screening method

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hepatocytes suspended in serum, Drug Metab Dis 28:1518-1523(2000).

Snyder WS et al (eds.). 'Report of the Task Group on Reference Man,'

Pergamon Press, Oxford/NY et al, 1975.

Stadtman ER, Protein oxidation and aging, Science 257:1220-1224(1992).

Stahl, WR, Scaling of respiratory variables in mammals. J Appl Physiol

22:453-460, 1967.

Tang, H, Mahmood I, Boxenbaum H, Mayersohn M. An improved model for

prediction of human clearance by allometric scaling, presented at the

November, 2003 annual AAPS Meeting in Salt Lake City, Utah, 2003.

Yates FE, Kugler PN, Similarity principles and intrinsic geometries:

Contrasting approaches to interspecies scaling, J Pharm Sci

75:1019-1027(1986)

Harold Boxenbaum, Ph.D.

Pharmacokinetics Consultant

Arishel Inc.

14621 Settlers Landing Way

North Potomac, MD 20878-4305

(P) 301-424-2806

(F) 301-424-8563

harold.-a-.arishel.com

www.arishel.com

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