Department of Physical Pharmacy and Pharmacokinetics Poznań University of Medical Sciences Pharmacokinetics laboratory

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1 Deprtment of Physicl Phrmcy nd Phrmcoinetics Poznń University of Medicl Sciences Phrmcoinetics lbortory Experiment 1 Phrmcoinetics of ibuprofen s n exmple of the first-order inetics in n open one-comprtment body model. Simultneous fitting of two dt sets - blood nd urine by mens of TopFIT.0 softwre Theoreticl nowledge: One-comprtment body model, drug concentrtion in blood nd urine fter single orl dose, clcultion of phrmcoinetic prmeters: K,, V d, Cl, AUC 00 mg of ibuprofen in single orl dose hs been dministered to ptient. The concentrtions of the drug in plsm nd urine re shown in the tble 1 nd. Tble 1. The chnge of concentrtion of ibuprofen in plsm Time [h] Concentrtion [mg/l] Tble. The chnge of concentrtion of ibuprofen in urine Time [h] Concentrtion [mg/l] Urine volume [ml] Plot the drug concentrtions in plsm versus time on grph pper. Clculte the bsorption nd elimintion rte constnts ( nd K) using the method of residuls 1

2 Deprtment of Physicl Phrmcy nd Phrmcoinetics Poznń University of Medicl Sciences Phrmcoinetics lbortory Methods of residuls The method of residuls is used in phrmcoinetics for resolving curve into its vrious exponentil components. The terms fethering, peeling nd stripping re lso used to described this technique. A drug dministered orlly is bsorbed by pprent first-order inetics nd confers the chrcteristics of one-comprtment model on the body. The following eqution (Btemn) hs been employed to describe the time course for such drug in the body: F X 0 K t t C = ( e e ) (1) V ( K) where C is the plsm concentrtion of drug t ny time t following the dministrtion dose X 0, V is the pprent volume of distribution, F is the frction of the orlly dministered dose which is bsorbed, nd nd K re the pprent first-order bsorption nd elimintion rte constnt, respectively. A plot of the logrithm of plsm drug concentrtion versus time following orl dministrtion will be biexponentil with terminl liner phse hving slope of K. Above eqution cn be trnsformed into the following expression: C = B e -K t A e - t () where A nd B re intercepts on the y xis for ech exponentil segment of the curve. Assuming >> K ( /K 3), the vlue for the second exponentil will become insignificntly smll with time (i.e., e - t 0) nd cn therefore be omitted. When this is the cse, drug bsorption is virtully complete. Eqution then reduces to: C = B e -K t (3) lnc = lnb K t () This eqution, which represents first order drug elimintion, will yield liner plot on semilog pper. The slope is equl to K, pprent first-order elimintion rte constnt. The vlue for cn be obtined by using the method of residuls. The Eq. 3 is substituted into the Eq. : - t C = C A e - t C - C = A e ln(c C) = lna - t (5) The new line obtined by grphing the logrithm of residul plsm concentrtion ginst time represents the phse. The slope is equl to, pprent first-order bsorption rte constnt. The vlues of K nd re obtined by the following procedure: ) Plot the drug concentrtion versus time on semilog pper with the concentrtion vlues on the logrithmic xis. b) Obtin the slope (), the y-intercept (b) nd regression coefficient of the terminl elimintion phse by lest squre method. The slope is equl to K. c) Clculte the extrpolted concentrtion vlues (C 1, C, C 3 nd C ) by substituting the time vlues t 1, t, t 3 nd t in the eqution where the slope nd the y-intercept were previously clculted.

3 Deprtment of Physicl Phrmcy nd Phrmcoinetics Poznń University of Medicl Sciences Phrmcoinetics lbortory d) Clculte the residul concentrtion vlues (C C) t the corresponding time points. A plot of the logrithm of the residul concentrtions versus time will yield stright line with slope of nd zero time intercept equl to lna. 3. Clculte: ) the hlf-life t0.5 = K b) C 0 from the elimintion curve C0 c) C 0 from the eqution: AUC =, if AUC = 13.8 mg h/l (determined by the K trpezoidl rule) F dose d) volume of distribution: V re = K AUC where F = V e) clernce: Cl = = K V t0.5 f) time (t mx ) needed to rech the mximum concentrtion C mx : 1 tmx = ln K K g) C mx from the Btemn eqution, using t mx vlue h) mounts of ibuprofen excreted in urine smples: i) cumultive mounts of ibuprofen in urine smples. TopFit TopFit is computer progrm for non-comprtmentl dt nlysis nd liner nd non-liner comprtmentl modeling with the option of simultneous effect fitting. TopFit llows simultneous nlysis of severl dt sets. Also, simultions of plsm levels nd effect inetics cn be performed. Enter the plsm concentrtion nd the cumultive mount of drug in urine into the TopFit by using the following procedure: I. MAIN MENU i. Edit heder () sve (F1) ii. Edit dt (5) 1. FORMULATION DATA. Type of input (Absorption/tblet) b. Nme of formultion (ibuprofen in plsm) c. Edit dosing tble (F7) i. Unit of time (h), unit of dosing (mg/individul), time = 0 h, Dose = 00 mg ii. Sve (F1) d. Edit dt sets (F8) i. Smple mtrix (plsm), type of weighting function (1/y ), unit of mesurement (mg/l), unit of time (h) ii. Sve (F1) e. Edit dt sets (F8) tble (F8) i. File the mesurement tble (time, concentrtion vlue) ii. Sve (F1). New (F6) 3. Enter the cumultive mounts of ibuprofen in urine 3

4 Deprtment of Physicl Phrmcy nd Phrmcoinetics Poznń University of Medicl Sciences Phrmcoinetics lbortory II.. Type of input b. Nme of formultion (ibuprofen in urine) c. Edit dosing tble (F7) i. Unit of time (h), unit of dosing (mg/individul), time = 0 h, Dose = 00 mg ii. Sve (F1) d. Edit dt sets (F8) i. Smple mtrix (urine), type of weighting function (1/y ), unit of mesurement (mg), unit of time (h) ii. Sve (F1) e. Edit dt sets (F8) tble (F8) i. File the mesurement tble (time, cumultive mounts) ii. Sve (F1) 3 MAIN MENU i. Enter methods menu (8) ii. Stndrd comprtment models () iii. One comprtment (1) iv. Select dt sets (1) 1. Select both formultions. Redy (F1) v. Strt itertion (6) vi. vii. Results Menu 1. View grphics (). Chnge Y-xis to logrithmic Edit (F3) b. Grph (F1) c. Exit (F10). View results (1). select s follows: Residuls; Prmeters, eigenvlues nd coefficients b. Sve (F1) Rewrite the vlues of phrmcoinetic prmeters Lg Time (t lg ) In some individuls, bsorption of drug fter single orl dose does not strt immeditely, due to such physiologic fctors s stomch-emptying time nd intestinl motility. The dely prior to the commencement of first-order drug bsorption is now s lg time. The lg time for drug my be observed if the two residul lines obtined by fethering the orl bsorption plsm level-time curve intersect t point greter thn t = 0 on the x xis. The time t the point of intersection on the x xis is the lg time. The lg time, t 0 represents the beginning of drug bsorption nd should not be confused with phrmcologic term onset time, which represent ltency, e.g., the time required for the drug to rech minimum effective concentrtion. Plsm level Lg Time C C C C Time

5 Deprtment of Physicl Phrmcy nd Phrmcoinetics Poznń University of Medicl Sciences Phrmcoinetics lbortory If we te under considertion the lg time the eqution 1 becomes: F X 0 K ( t tlg ) ( t tlg ) C = ( e e ) (6) V ( K) 5. Compre the vlues obtined using the method of residuls with those obtined by Topfit. Discuss the differences. References: 1. Rosenbum S.E.: Bsic Phrmcoinetics nd Phrmcodynmics. An Integrted Textboo nd Computer Simultions. John Wiley&Sons, Inc., Shrgel L. Wu-Pong S., Yu A.B.C. Applied biophrmceutics & phrmcoinetics.mcgrw Hill Burton M.E., Shw L.M., Schentg J.J., Wilims W.E.: Aplied Phrmcoinetics &Phrmcodynmics. Lippincott Willims & Wilins, th edition, Tozer T.N., Rowlnd M.: Introduction to phrmcoinetics nd phrmcodynmics.the Quntittive bsis of drug therpy. Lippincott Willims & Wilins, Winter M.E: Bsic Clinicl Phrmcoinetics. Lippincott Willims&Wilins th edition,