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Tolbutamide (Problem 1)

Miners J, Foenander T, Wanwimolruk S, Gallus A, Birkett D. (European Journal of Clinical Pharmacology) The effect of sulphin-
pyrazone on oxidative drug metabolism in man: inhibition of tolbutamide elimination (1982) 22: 321-326.

About the drug: Tolbutamide is a sulfonylurea which has been used as an oral hypoglycemic agent in non-
insulin-dependent Diabetes Miletus with adult onset. In a study using normal, healthy, 70 kg volunteers the
following pharmacokinetic data was obtained. Tolbutamide is well absorbed. It is highly protein bound
(96%). The volume of distribution is 0.143 L/kg with a half-life of 6.93 hours in normal adults. Tolbutamide
is cleared entirely by hepatic function. Dosing: Tolbutamide (Orinase-brand name) is manufactured by
Upjohn. Both 250 and 500 mg tablets are manufactured. Both tablet sizes are available for prescription use.
The normal daily dose should not exceed 3 grams. Your consult should contain both an aggressive and
conservative dosage regimen recommendations when appropriate as well as calculations where appro-
priate.
Extraction ratios are calculated for normal individuals and are considered to be constant.
Qr = 0.0191 L/min/kg, Qh = 0.0238 L/min/kg.
Bioequivalence: In a study presented to you (Int J Clin Pharmacol Ther 1997 Jan; 35(1):43-6) A 500 mg
brand name tablet yielded an AUC of 499 mg/L *hr while a 500 mg generic tablet yielded an AUC of 498
mg/L *hr . The Cpmaxs were 55.1 vs 58.8 mic/mL and the Tmaxs were 4.55 vs 3.82 hr respectively. The
generic comes in 250 and 500 mg scored tablets and cost approximately 1/3 of the brand name. You have
been asked to prepare a recommendation for the P & T Committee for inclusion into the formulary for the
HMO. Please give your recommendation and support it with appropriate documentation.
(Short paragraph)

(Important variables and constants)

(Use other side for supportive documentation - appropriate calculations)

Basic Pharmacokinetics REV. 98.10.22 -1


Copyright © 1996 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
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Elderly: Tolbutamide is mainly used for the treatment of middle aged and elderly patients. It is well docu-
mented that plasma albumen levels decrease with increasing age. This produces a net decrease in protein
binding equivalent to 92%, with no change in drug half-life or volume of distribution. Please prepare an ini-
tial consult for KT a 75 y/o, 70 kg, healthy male. Your consult should contain both an aggressive and conser-
vative dosage regimen recommendation which attempts to attain the free tolbutamide concentration range of
normal, healthy volunteers who were dosed at 250 mg TID as well as a short explanation of the observations.
(Short paragraph)

(Important variables and constants)

(Use other side for supportive documentation - appropriate calculations)

Basic Pharmacokinetics REV. 98.10.22 -2


Copyright © 1996 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
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Concomitant treatment: Sulphinpyrazone, a drug used as an antithrombotic agent and inhibitor of platelet
aggregation has a potent side effect as a uricosuric agent. The uricosuric side effect increases the urinary
excretion of uric acid effectively blocking hepatic conjugation. Tests show that Sulphinpyrazone’s effect on
Tolbutamide is a reduction of liver function (Clinth*/Clinth = 0.6) to 60% of normal without interfering with
protein binding. Please prepare a dosage regimen consult for LM, an otherwise normal, 90 kg adult who was
maintained on 250 mg Orinase QID prior to taking this new drug as well as a short explanation of the obser-
vations.
(Short paragraph)

(Important variables and constants)

(Use other side for supportive documentation - appropriate calculations)

Basic Pharmacokinetics REV. 98.10.22 -3


Copyright © 1996 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
::

Systemic Alkalosis: Gastric acid loss caused by vomiting is a concern for the hypoglycemic patient using
Tolbutamide. Tolbutamide’s molecular structure contains an active sulfonamide group which ionizes at
increased plasma pH levels associated with metabolic alkalosis from gastric acid loss in vomition. Because of
this ionization Tolbutamide protein binding to alpha1-acid glycoprotein is increased to 98%, with a decrease
in volume of distribution to 6.375 L. Please prepare a dosage regimen consult for AM, an otherwise normal,
80 kg adult who was maintained on 250 mg Orinase TID prior to this problem as well as a short explanation
of the observations. .
(Short paragraph)

(Important variables and constants)

(Use other side for supportive documentation - appropriate calculations)

Basic Pharmacokinetics REV. 98.10.22 -4


Copyright © 1996 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
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Viral Hepatitis: Viral hepatitis causes a 72.5% increase in volume of distribution while and decreasing the
protein binding to 92% and the hepatic function by 25% (Clinth*/Clinth = 0.75). Please prepare a dosage reg-
imen consult for BE, an otherwise normal, 55 kg adult who was maintained on 250 mg Orinase BID prior to
this problem as well as a short explanation of the observations..
(Short paragraph)

(Important variables and constants)

(Use other side for supportive documentation - appropriate calculations)

Basic Pharmacokinetics REV. 98.10.22 -5


Copyright © 1996 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
::

161) Are the tablets bioequivalent? Why/ Why not?

Patient Normal Elderly Concomitant Systemic Viral Hepati-


Condition Treatment Alkylosis tis
Dose(mg) 500 mg 500 mg 500 mg 72) ??? mg tablet 92) ??? mg 115) ??? mg 138)??? mg
IV Brand tablet Generic tablet tablet tablet tablet
f 1) 22) 49) 73) 93) 116) 139)
fu 2) 23) 50) 74) 94) 117) 140)
Vd (L) 3) 24) 51) 75) 95) 118) 141)

k (hr-1) 4) 25) 52) 76) 96) 119) 142)

T 1/2 (hr) 5) 26) 53) 77) 97) 120) 143)


AUC (mg/L*hr) 6) 27) 54) 78) 98) 121) 144)
2) 7) 28) 55)
AUMC (mg/L*hr
MRT 8) 29) 56)
MAT 30) 57)
Ka 31) 58)
Peak Time 9) 32) 59)

Cl tot (L/hr) 10) 33) 60) 79) 99) 122) 145)

Cl h (L/hr) 11) 34) 61) 80) 100) 123) 146)

Cl r (L/hr) 12) 35) 62) 81) 101) 124) 147)

Eh 13) 36) 63) 82) 102 125) 148)

Er 14) 37) 64) 83) 103) 126) 149)

Cl h (L/hr) 15) 38) 65) 84) 104) 127) 150)


int

Cl r (L/hr) 16) 39) 66) 85) 105) 128) 151)


int

FR h 17) 40) 67) 85) 106 129) 152)

FI h 18) 41) 68) 87) 107) 130) 153)

FR r 19) 42) 69) 73) 108) 131) 154)

FI r 20) 43) 70) 77) 109) 132) 155)

FCL 21) 44) 71) 81) 110) 133) 156)

τ (hr) 45) 85) 111) 134) 157)

N 46) 89) 112) 135) 158)


47) 90) 113) 136) 159)
ss µg-
 -------
Cp
max f ree  mL

48) 91) 114) 137) 160)


ss µg-
 -------
Cp
min free  mL

Basic Pharmacokinetics REV. 98.10.22 -6


Copyright © 1996 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/