basic pharmacokinetics - tamide exam

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Basic Pharmacokinetics REV. 98.10.22 -1Copyright © 1996 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/

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 thefollowing 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. Tolbutamideis cleared entirely by hepatic function. Dosing: Tolbutamide (Orinase-brand name) is manufactured byUpjohn. 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 andconservative 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 mgbrand name tablet yielded an AUC of 499 mg/L *hr while a 500 mg generic tablet yielded an AUC of 498mg/L *hr . The Cpmaxs were 55.1 vs 58.8 mic/mL and the Tmaxs were 4.55 vs 3.82 hr respectively. Thegeneric comes in 250 and 500 mg scored tablets and cost approximately 1/3 of the brand name. You havebeen asked to prepare a recommendation for the P & T Committee for inclusion into the formulary for theHMO. Please give your recommendation and support it with appropriate documentation.

(Short paragraph)

(Important variables and constants)

(Use other side for supportive documentation - appropriate calculations)

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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 proteinbinding 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 ofnormal, healthy volunteers who were dosed at 250 mg TID as well as a short explanation of the observations.

(Short paragraph)



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Concomitant treatment: Sulphinpyrazone, a drug used as an antithrombotic agent and inhibitor of plateletaggregation has a potent side effect as a uricosuric agent. The uricosuric side effect increases the urinaryexcretion of uric acid effectively blocking hepatic conjugation. Tests show that Sulphinpyrazone’s effect onTolbutamide is a reduction of liver function (Clinth*/Clinth = 0.6) to 60% of normal without interfering withprotein binding. Please prepare a dosage regimen consult for LM, an otherwise normal, 90 kg adult who wasmaintained on 250 mg Orinase QID prior to taking this new drug as well as a short explanation of the obser-vations.

(Short paragraph)



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Systemic Alkalosis: Gastric acid loss caused by vomiting is a concern for the hypoglycemic patient usingTolbutamide. Tolbutamide’s molecular structure contains an active sulfonamide group which ionizes atincreased plasma pH levels associated with metabolic alkalosis from gastric acid loss in vomition. Because ofthis ionization Tolbutamide protein binding to alpha1-acid glycoprotein is increased to 98%, with a decreasein 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 explanationof the observations. .

(Short paragraph)



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Viral Hepatitis: Viral hepatitis causes a 72.5% increase in volume of distribution while and decreasing theprotein 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 tothis problem as well as a short explanation of the observations..

(Short paragraph)



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

Patient Condition

Normal Elderly Concomitant Treatment

Systemic Alkylosis

Viral Hepati-tis

Dose(mg) 500 mg IV

500 mg Brand tablet

500 mg Generic tablet

72) ??? mg tablet 92) ??? mg tablet

115) ??? mg tablet

138)??? mg 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)

AUMC (mg/L*hr2) 7) 28) 55)

MRT 8) 29) 56)

MAT 30) 57)

Ka 31) 58)

Peak Time 9) 32) 59)

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

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

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

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

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

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

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

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

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

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

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

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

(hr) 45) 85) 111) 134) 157)

N 46) 89) 112) 135) 158)

47) 90) 113) 136) 159)

48) 91) 114) 137) 160)

Cltot

Clh

Clr

Eh

Er

Clhint

Clrint

FRh

FIh

FRr

FIr

τ

Cpss

maxfree

µgmL--------

Cpss

minfree

µgmL--------

basic pharmacokinetics - tamide exam

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