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Pharmacological Research Communications, Vol. 16, No. 7, 1984 723 PHARMACOKINETIC STUDY ON INTRAVENOUS RIFAMPICIN IN MAN ,, Acocella G. , Segre G. , Conti R. . , . , Pagani P. V. , Pallanza R. , Perna G. and Simone * ** *** Lepetit Research Laboratories, Milan Siena Institute Locatelli of Pharmacology Hospital of the University, (Bergamo) - Groppino Received m final ~ r m 2February 1984 SUMMARY A pharmacokinetic to assess study was c a r r i e d o u t concentrations doses in
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  Pharmacological Research Communications, Vol. 16, No. 7, 1984 723 PHARMACOKINETIC STUDY ON INTRAVENOUS RIFAMPICIN IN MAN Acocella G. , Segre G.,, . , . , Conti R. , Pagani V. , Pallanza R. , Perna G.and Simone P.* Lepetit Research Laboratories, Milan** Institute of Pharmacology of the University, Siena*** Locatelli Hospital - Groppino (Bergamo) Received m final ~rm 2February 1984 SUMMARY A pharmacokinetic study was carried out in 18 male patients in orderto assess the blood concentrations of rifampicin after intravenous ad-ministration of 3 different doses (600, 900 and 1200 mg)over 3 diffe-rent periods of infusion (1, 2 and 3 hours). The results show that, by increasing the dose and the rate of infusionhigher and earlier peak concentrations are obtained.A kinetic analysis based on a one-compartment open model gives a goodfitting of the data obtained experimentally.From these data one obtains for the volume of distribution a value of48.1 + 1T.2 liters and for the serum disappearance rate the value of-I0.212 + 0.070 h in adult subjects.It is possible to predict the time course of serum kinetics of thedrug by using the equation kC(t) = o (1 -e -0 21 t)20 (t = hours, k o -1= infusion rate in mg h ). 0031-6989/84/070723-14/$03.00/0 © 1984 The Italian Pharmacological Society  724 Pharmaco~gical Resea~h Commun~ations, VoL l~ No. Z 1984 IntroductionPrevious studies have been carried out to assess the time course o¢the serum levels of rifampicin (RAMP) in man during and after admi-nistration of doses ranging from 150 to 600 mg by intravenous infu-sion (Acocella G. et al., 1977; Nitti V. et al., 1977).Of the three main variables characterizing an i.v. infusion, namelythe dose, the volume of solution to be injected, and the duration ofinfusion, only one was changed in such studies (the dose), the othertwo remaining constant (volume = 500 ml and duration of infusion = 3 hours).Under these experimental conditions the results indicated that thereis a good similarity between the serum concentrations obtained afteradministration of the same dose by the oral and the intravenous route,a fact which indicated the high degree of absorption of rifampicinfrom the gastro-intestinal tract.The present study was undertaken in order to evaluate the pharmaco-kinetics of RAMP when two of the three variables were modified, namelythe dose and the duration of infusion, keeping the volume of the so-lution constant. Material and Methods1) Subjects. The study was carried out on a group of 18 male patientsnot suffering from diseases or syndromes known or likely to alterthe kinetics of the antibiotic and who could benefit from the admi-nistration of rifampicin. Informed consent was obtained from eve-ry patient. Each patient received one infusion according to thescheme described below.2) Treatment. Lyophilized RAMP (300 mg and 600 mg vials) was dissolvedin the appropriate solvent (5 ml and 10 ml respectively) and addedto a 500 ml of 5%glucose solution for phleboclysis.A dose of 600, g00, and 1200 mg was used.  Pharmacologicel Research Communications, Vol. 16, No. Z 1984 725 3) Administration scheme. As sa~d in the introduction, two variableswere modified, the dose and the Pate of infusion. The dose levelstested were 600, g00 and 1200 mg, each dose being administered in aconstant volume in 3 hours, 2 hours and 1 hour. Dose (mg) 600600600 go0go0go0120012001200i uration of infusion (h) 3 2 1321Each treatment was administered to 2 patients and each patient recei-ved a single infusion in order to get serum concentration curves un-affected by possible changes due to effects of self-induction (Aco-cella G., Mattiussi R., Segre G., 1978).In all cases, the infusion was carried out without the aid of arti-ficial means of constant administration 6constant infusion pump).4) Method of assay. Rifampicin concentrations were assayed in serumwith the agar-plate method using Sarcina lutea ATCC 9341 as testmicroorganism (Furesz S. et al., IgTT),5) Kinetic analysis. For each patient and scheme of administrationa comparison was carried out between the experimental serum con-centration data and those calculated according to the equationreported below.For each patient the parameters of one-compartment open model weredetermined from the observed concentrations, with a constant rateof entry of the antibiotic in blood (k) which was known and was de-opending on the administration scheme. On the basis of these para-  726 Pharmacological Research Communications, VoL 16, No. 7, f984 nleters, a fitting of the experimental data was performed for each case, The blood samples were taken at time O, and then at 10; 30; 60; 90 minutes, and 2; 4; 8 hours from the beginning of the infusion. The mathematical model isdC/dt = -K C + k /V for 0 4 t 4 T (during the infusion)odC/dt = -K C for t ~ T (after the infusion)(C = serum concentration of RAMP (~g:ml); t = time in hours; T = infu-sion time; V = volume of distribution in ml; K = eliminatxon constant;-1k = Dose/T = infusion rate, in mg h ).oThe solution of this model is given by the equations: koC : (I - e -Kt) for 0 ~ t ~ T (1) V.Kand k o -KT -K(t - T) -K(t -T)C = (1 - e ) e = C(T) e for t~ T (II)V.KThe asymptotic value of C can be calculated to be: ko c( ~ ) ....... (zzz) V.Kin this case (when the infusion is carried out for an enough long time) a steady state is reached from which one obtains k = C (o.,:~) . V.K (IV) o The value of V can be calculated from eq. (IV), being V = from the equation V.K°k o orC(c~cm) ,K Dose = Clearance, by noting that: Clearance =C.dtoThe experimental data were fitted to the model by using digital computingtechiniques and the SAAM-27 program (Berman M.,Weiss M.F., 1974).
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