Implications of Intraindividual Variability in Bioavailability Studies of Furosemide

Transcription

1 Eur J Cln Pharmacol (1984) 27: European Journal of Clncal Pharmacology Sprnger-Verlag 1984 Implcatons of Intrandvdual Varablty n Boavalablty Studes of Furosemde A. Grahnrn 1, M. Hammaflund 2, and T. Lundqvst 1 1Department of Drugs, Natonal Board of Health and Welfare, and/department of Bopharmaceutcs and Pharmacoknetcs, Unversty of Uppsala, Uppsala, Sweden Summary. Intrasubject varaton n boavalablty (rate and extent) and dsposton of furosemde 40 mg was nvestgated usng a repeated, randomzed, double-blnd cross-over study n 8 healthy subjects. Two generc tablet formulatons (Lasx and Furx) and ntravenous furosemde were compared on 6 separate days. Extensve ntrasubject varablty after oral admnstraton was observed n AUC, mean absorpton tme (MAT) and urnary excreton. The varablty (error varance) wthn the dosage forms was as large as that between the two genercs. These varatons most probably depended on the absorpton process, snce the repeated.v. doses showed only margnal ntrasubject varablty. Absolute boavalablty was 56% for Lasx and 55% for Furx (AUC). The range was 20 to 84% between ndvduals and the maxmal range wthn one ndvdual was 20 to 61%. Confdence nterval and Bayesan analyss showed a hgh probablty of non-equvalence not only between but also wthn the genercs when the separate cross-over experments were analyzed (8 observatons). When extendng the analyss to 16 observatons, boequvalence was demonstrated for the two generc tablets. Rate of absorpton, quantfed as MAT, was 128 mn for Lasx and 98 mn for Furx (16 observatons). Snce MAT was sgnfcantly longer (p < 0.001) than the mean resdence tme after the.v. dose (57 mn), absorpton was evdently the ratelmtng step n the overall knetcs of oral furosemde. Intrandvdual varaton n absorpton s a confoundng factor n boavalablty studes of furosemde usng lmted numbers of subjects. Ths s mportant to consder when desgnng and evaluatng boavalablty studes for drugs showng these varatons. Key words: furosemde; boavalablty, generc tablet formulatons, ntrasubject varablty The recognton of drug bonequvalence n the early 70's for generc drugs dentfed drug boavalablty as a practcal problem on whch success or falure of drug therapy frequently depends [1, 2]. The problem was also recognzed by drug regulatory authortes as generc products represent an mportant part of the drug market. Regulatory bodes have therefore ssued regulatons to ensure boequvalence of genetc drugs [3, 4]. Methods for comparatve boavalablty studes n man comprse cross-over desgns n randomzed complete or ncomplete blocks. These desgns am to optmse the analyss of the results, ncludng adequate statstcs [5]. One of the basc assumptons n cross-over trals s that the ndvdual s constant n hs/her clearance of the drug from day to day. When comparng dfferent dosage forms t s also assumed that the absorpton processes are constant wthn the ndvdual. Thus, any dfferences observed should be related to the dosage forms. However, n the vast majorty of publshed (and unpublshed) boavalablty studes these assumptons are rarely challenged. It has been reported that furosemde may exhbt large ntrasubject varaton n boavalablty [6]. Therefore, a study has been undertaken to dentfy the presence and nature of ntrasubject varablty n the boavalablty of furosemde and ts mplcatons when comparng two generc dosage forms, usng a repeated complete block cross-over desgn. Materals and Methods Subjects Eght healthy volunteers, 4 men and 4 women, aged 25 to 27 years, and weghng 53 to 82 kg, gave ther nformed consent to partcpaton n the study, whch was approved by the Ethcs Commttee at the Unversty Hosptal of Uppsala. All subjects underwent

2 596 A. Grahntn et al.: Varablty n Boavalablty of Furosemde routne medcal examnaton ncludng blood pressure, medcal hstory, urne analyss and S-creatnne. Two subjects were nfrequent tobacco users; they dd not smoke durng expermental days. Desgn The boavalablty of two generc tablet formulatons of furosemde was compared n a randomzed, double-blnd cross-over study, n a repeated complete block desgn. Furx 40 mg, batch no.91926, and Lasx 40 mg, batch no. 167 WO 83, were used. Intravenous furosemde (Impugan 10mg/ml) was also admnstered on two dfferent occasons. Each subject partcpated n sx experments separated by at least one week. The dose on all occasons was 40 mg. The experments started at 7.30 a.m. No drugs were allowed one week before and no alcohol for 2 days before the expermental days. The subjects were also nstructed to avod very salt food n the 24 h before the experment and untl the last urne sample was collected. The drugs were gven after an overnght fast. No food was allowed untl 4 h after drug admnstraton, when a standardsed lunch was served, correspondng to a total Na + and K + ntake of 48 and 30 mmol, respectvely. ml tap water was gven every hour for 7 h and 100 ml was gven wth the dose. Seven hours after the dose, the subjects were allowed food and lqud (not alcohol) ad lbtum. Blood samples were taken at regular ntervals for 7 h through an ndwellng forearm cannula (Venflon) nto heparnzed Venoject tubes. Intravenous furosemde was admnstered n the contralateral arm. The blood samples were left n room temperature for 20mn before plasma was harvested. The plasma was frozen and stored at -20 C untl analysed. Urne was collected as voded for 24 h. The urne from 7 to 24 h after the dose was pooled. Furosemde Analyss The concentratons of furosemde n plasma and urne were measured by HPLC wth fluormetrc detecton [7]. 0,25-0,5 ml plasma and 0,1 ml urne were used n the assay. The determnaton lmt of the assay was 20 ng/ml. In plasma, the reproducblty of the assay was + 5,5% (50 ng/ml) and 4,3% ( ng/ ml); n urne t was 5,9% (2 Bg/ml). The assay procedure was performed n such a way as to mnmze photochemcal and acd degradaton of furosemde. Pharmacoknete Analyss The followng calculatons were made: Clearance (CL)= Dose.v. AUC.v. Volume of dstrbuton at steady state (Vdss) = Dose.v. x AUMC AUC 2 Absolute boavalablty (F) = AUCora Dose.v. AUCLv. x Doseoral AUC and AUMC for the ndmdual curves were calculated by the trapezodal rule up to the last data pont. The extrapolated area to nfnte tme for AUC and AUMC beyond the last data pont was estmated by ntegraton. Extent of Absorpton Comparson of the extent of absorpton of the dfferent dosage forms after oral admnstraton was based on AUC and urnary excreton measurements. Rate of Absorpton Statstcal moments [8, 9, 10] were used as a modelndependent way of estmatng the tme course of absorpton and dsposton of furosemde. f tcdt AUMC Mean Resdence Tme (MRT)= o = AU-----C f Cdt 0 Mean Absorpton Tme (MAT) -- MRToral- MRT.v. Statstcal Analyss Two way analyss of varance for balanced data (ANOVA) was used to test for dfferences between dosage forms. To test for boequvalence, symmetrcal confdence ntervals accordng to Westlake [11, 12], and Bayesan analyss accordng to Rodda and Davs [13], were used. Lasx was used as the reference drug. All results are gven as mean + SD. Results Extent of Absorpton - A UC The total AUCs found after repeated oral and ntravenous admnstraton of 40 mg furosemde to the 8 subjects are summarsed n Table 1. Large nterand ntra-ndvdual varaton were found after oral admnstraton. The absolute boavalablty was 56+18% for Lasx and 55+12% for Furx, respectvely. The range was 20 to 84% between ndvduals, and the maxmal range wthn one ndvdual was 20 to 61%. Data from one subject gven each dosage form n a repeated cross-over desgn are shown n Fg. 1. The plasma concentraton-tme profles were totally df- rx~

3 A. Grahn~n et al.: Varablty n Boavalablty of Furosemde 597 Table 1. Total AUC [~tg/ml/mn] after oral and ntravenous admnstraton of furosemde, 40 mg on two dfferent occasons Subject Lasx (1) Lasx (2) Furx (1) Furx (2).v. (1).v. (2) AH AL DL EA ES ME MS UB Mean ±SD I~00 1 : "~", ~ LASIX - 1 *---* FURIX- I! ~E I1000 c E 11,2 600 It ~00.r. : LASIX-2 *'"* FURIX-2 1 ~I000 E S,00 LL 600 t,00, " I I I I I I I I 2 3 ~ tme {h) Fg. 1. Plasma concentratons of furosemde n one ndvdual gven Lasx and Furx tablets (40 mg) as a sngle oral doses on two dfferent occasons (repeated cross-over test) ferent n the two experments. In the frst cross-over experment (top) Furx showed more complete boavalablty than Lasx, whereas the contrary was found n the second experment (bottom). Some ndvduals (two shown n Fg. 2) showed the same absorpton from the two dosage forms. An example of extreme ntrandvdual varaton n boavalablty of furosemde from the same dosage form (same batch) s shown n Fg. 3. Statstcal analyss of the AUC data s summarzed n Table 2. Due to the large nter- as well as ntra-ndvdual varablty, no statstcally sgnfcant dfference n AUC could be detected (ANOVA). However, confdence nterval and Bayesan analyss

4 598 A. Grahn6n et al.: Varablty n Boavalablty of Furosemde = m OO 400 / "*"-..~ = E 1000 w 800 6O I 0..j / / 1 I I... I I 1 I tme(h) Fg.2. Plasma concentratons of furosemde n two ndvduals (top and bottom) gven Lasx and Furx tablets as sngle oral doses on one occason (cross-over test, second perod) O O Lasx-2; * * Furx- 2 ndcated a hgh probablty of non-equvalence not only between but also wthn dosage forms when the separate cross-over experments were analyzed (8 observatons). The relatve error varance was of the same magntude wthn as well as between dosage forms. From Table 2 t can be seen that usng 16 observatons, confdence ntervals decreased to 19% and the probablty of a true 20% dfference between dosage forms was only 6%. Intrandvdual varaton n AUC after ntravenous admnstraton was substantally smaller than after oral admnstraton, the relatve error varance beng of the order of only 5% of that found after oral dosng. The maxmal devaton of the plasma concentratons of furosemde observed n one ndvdual when 40 mg furosemde was gven ntravenously at two occasons s llustrated n Fg. 4. Extent of Absorpton - Urnary Excreton Urnary excreton of unchanged furosemde (24 h) was mg after ntravenous admnstraton and 16.2+_3.6 and 16.2+_3.1 mg after Lasx and Furx, respectvely. The absolute boavalablty calculated from urnary excreton data was therefore n good agreement wth the boavalablty based on AUC. Urnary excreton (oral) ranged from 7.8 to 23.0 mg between ndvduals and the maxmal range wthn one ndvdual was 7.8 to 13.0mg for Lasx and 12.0 to 23.0 mg for Furx, respectvely. Statstcal analyss of the urnary excreton results showed the same pattern as the AUC data. Confdence ntervals were _ 22% (mean value) between dosage forms and +_ 26% (Furx) and + 23% (Lasx) wthn dosage forms (8 observatons). When extendng the analyss to 16 observatons the confdence ntervals decreased to + 14% between dosage forms.

5 A. Grahn6n et al.: Varablty n Boavalablty of Furosemde ~I000.'9 800 E m o 600 LL 400 ". \ /.',._j -. c : LASIX-1 *---* LASIX-2 ~. --e 1600 J ~ooo- I 1 H *'-'* FURIX-1 FURIX-2 8,00- E o 600" LL " 0 f ~ r \ " " I 1 l 1 1 I I tme(h) Fg.3. Examples ofntrandvdual varaton n the plasma concentratons of furosemde n two subjects (top and bottom) gven Lasx and Furx tablets, respectvely, on two dfferent occasons (repeated cross-over test) Table 2. Confdence nterval and Bayesan analyss of AUC-data followng repeated ntravenous and oral admnstraton of 40 mg furosemde Admnstraton Number of Confdence Probablty observatons nterval [%] of a 20% dfference [%].v. (1) -.v.(2) 8 ± Lasx (1)-Furx (1) 8 ± Lasx (2)-Furx (2) Lasx (1)-Lasx (2) Furx (1)-Furx (2) 8 ± Lasx -Furx Rate of Absorpton The average mean resdence tme after.v. admnstraton of furosemde was ran (Table 3). The average mean absorpton tme was mn for Lasx and mn for Furx (N. S., 16 observatons), respectvely. The areas under the curve for the.v. dose from the last data pont to nfnty for total AUC and AUMC were 0.5 to 3.5%, and 3.6 to 21 (mean 11)% respectvely. For the oral doses they were 0.8 to 17 (mean 5,8)%, and 3.6 to 48 (mean 15)%, respectvely. In the calculatons of the extrapolated AUMC for the.v. dose, an error was ntroduced for some ndvduals when basng the calculatons on the fnal slope (last 3-4 data ponts). Then, the last 6-7 data ponts were used n order to stablze the calculatons of total AUMC. Confdence nterval analyss (Table 4) showed a very small confdence nterval for the.v. dose between the 2 treatment days. The MRT for Day 2 was wthn +6 ran of the value for Day 1. However, when lookng at the oral doses, the confdence nterval for MAT was much larger (51 to 95 mn). The varaton for MAT was as large when one dosage form was compared between days (ntrandvdual varaton) as when Lasx and Furx were compared. The large confdence ntervals ndcated non-equvalence of the rate of absorpton of the generc tablets when analyzng the separate experments. In contrast

6 600 A. Grahnrn et al: Varablty n Boavalablty of Furosemde 10 0.I _ t, - - x , tme(ran) Fg.4. Example of maxmal ntrandvdual varaton n the plasma concentratons of furosemde n one subject gven ntravenous furosemde (40 mg) on two dfferent t_ occasons Table 3. Indvdual mean resdence tmes (. v.) and mean absorpton tmes of furosemde. In the calculatons of MAT, a mean value of MRT.v. for Days 1 and 2 was used Subject Intravenous dose Lasx Furx MRT, v, MRT.v. MAT MAT MAT MAT (1) (2) (1) (2) (1) (2) AH AL 71, DL 53, EA 4t ES ME MS UB Observatons Mean tll _+ SD 10.8 t2.2 67, Observatons Mean ~ 98.1 a + SD "p < compared to MRT,,, to extent of absorpton, combned analyss (n = 16) dd not decrease the confdence ntervals of the rate of absorpton. Wth the current batches used, Furx seems to be more rapdly absorbed, than Lasx, although conventonal ANOVA dd not demonstrate sgnfcant dfference between the 2 tablets. Urne Volumes The urnary output (7 h) was 2.21 _ after ntravenous admnstraton and 1.90_ and after admnstraton of Lasx and Furx, respectvely. After oral admnstraton urnary volumes ranged from 1.08 to between ndvduals, and the maxmal range wthn one ndvdual was 1.56 to (Lasx), and 1.37 to (Furx). The confdence nterval based on eght observatons was 15% (mean) between dosage forms and + 24% (Lasx) and + 21% (Furx) wthn dosage forms, respectvely. When the statstcal analyss was extended to 16 observatons the mean urnary output after admnstraton of Furx was wthn _+ 11% of the mean urnary output after admnstraton of Lasx. Dscusson The most mportant fndng n the present study s the extensve ntrandvdual varaton both n the rate and extent of absorpton of furosemde from two oral dosage forms. Although strctly standardzed condtons were employed, and healthy volunteers and the same batches of the dfferent dosage forms were used, the magntude of the ntrandvdual varaton was n the same range as the nterndvdual varaton. The two dosage forms showed approxmately equal wthn-subject varaton, ndcatng that the dosage forms were "equvalent" n ths respect. The dsposton knetcs of furosemde followng ntravenous admnstraton, eg. volume of dstrbuton at steady-state (7.91), plasma clearance (139 ml/ mn), mean resdence tme (57mn) ]and urnary excreton of unchanged drug (70% of dose), was n good agreement wth prevous reports [14-17]. Thus, the fndngs are not lkely to be due to methodologcal ptfalls but rather they reflect real varaton. In most ndvduals, a trexponental declne n the plasma concentraton was evdent after the.v. doses. An error can be ntroduced n calculaton of AUMC when there s pronounced multcompart-

7 A. Grahn6n et al.: Varab!lty n Boavalablty of Furosemde 601 Table4. Confdence nterval and Bayesan analyss of mean resdence (MRT) and mean absorpton tmes (MAT) followng repeated ntravenous and oral admnstraton of 40 mg furosemde Admnstraton Number of observatons Confdence nterval Probablty of a 20% dfference [%] + [%] + [mn] MRTI.v. (1) -.~. (2) MAT Lasx (1)-Fufx (1) MAT Lasx (2)-Furx (2) MAT Lasx (1)-Lasx (2) MAT Furx (l)-furx (2) MAT Lasx -Furx aactual dfference exceeded 20% a a a mental behavour of the drug [18], dependng on dffcultes n calculatng the extrapolated area. Ths was also found n the present study. The t C values may even rse when the fnal slope declnes slowly, thus producng a large error n the AUMC calculatons. The AUC for the fnal slope n the plasma concentraton curve for furosemde has been shown to represent only about 10% of the total AUC [7]. Accordngly t was consdered justfed to use plasma concentraton values from the last two phases n calculatng the extrapolated area to dmnsh the potental error n calculaton of the AUMC. The prelmnary fndng of Dagrosa et al. [6], of extensve ntrasubject varaton n absorpton and/or dsposton of oral furosemde n two ndvduals has been confrmed n the present study. The results of the repeated ntravenous admnstratons showed substantally smaller ntrandvdual varatons than the oral admnstratons. Thus, the major source of varaton s most probably attrbutable to varaton n the rate and extent of absorpton. The mechansms behnd the extensve ntrasubject varaton n absorpton cannot be fully elucdated, snce an oral soluton was not employed n ths study. A contrbuton of day to day varaton n vvo dssoluton cannot be ruled out. The FDA has shown that the extent of absorpton of furosemde genercs s nfluenced by the n vtro dssoluton propertes [19]. However, consderng the results of Hammarlund et al. [7], of an erratc and varable absorpton profle of furosemde, a more lkely explanaton of our fndng s day to day varaton n physologcal factors affectng gastrc emptyng and gastrc ph. These factors by themselves mght nfluence both the rate and extent of absorpton of drugs, as well as the n vvo dssoluton profle of a specfc dosage form [20]. The erratc and dscontnuous plasma concentraton-tme profles after oral admnstraton prompted us to use moment analyss to evaluate the rate of absorpton. In fact, Hammarlund found t mpossble to obtan a meanngful estmate of the rate of absorpton usng a deconvoluton technque (unpublshed data). It was possble to confrm the results of Hammarlund et al. [7], that the MRT after ntravenous admnstraton was sgnfcantly shorter than the MAT after oral admnstraton of Lasx and Furx. Ths strongly ndcates that furosemde knetcs s ratelmted by absorpton. The mplcatons of ntrandvdual varatons n both the rate and extent of absorpton for the evaluaton of boavalablty studes of furosemde usng classcal cross-over desgns are evdent. As seen from Tables 2 and 4, the statstcal analyss ndcated a large probablty of non-equvalence not only between dosage forms but also wthn the same dosage form! Thus, ntrasubject varablty contrbuted to a large extent to the total varablty, thereby ndcatng that the true dfference between dosage forms was smaller. It was evdent that the two dosage forms could be consdered boequvalent wth regard to the extent of absorpton, acceptng a _+ 20% dfference (16 observatons; Table 2). Comparng the dfferent parameters, urne volume showed the smallest confdence ntervals. In healthy volunteers, the duretc effect of furosemde was hghly dependent on the water load gven to the subjects (unpublshed observatons). Ths makes duress a less senstve boequvalence parameter for detectng varatons n the extent and rate of absorpton of furosemde. It could be argued that f a substantally larger number of subjects had been ncluded, the nfluence of ntrasubject varablty would have been dmnshed. Ths would be true f t be assumed that the actual ntrasubject varablty had a normal dstrbuton. Usng the approach of Rodda and Davs [13], t could be calculated that between 20 to 37 subjects would have been requred n a non-repeated desgn to detect a true 20% dfference between the dosage forms wth a power of 80% (a = 0.05). Thus, to overcome the contrbuton of ntrasubject varablty as a confoundng factor n the analyss of boequvalence studes of furosemde, large numbers of subject would have to be ncluded n a classcal cross-over desgn. A repeated desgn, as used n ths study, has the advantage that the magntude of ntrasubject var-

8 602 A. Grahntn et al.: Varablty n Boavalablty of Furosemde ablty can be estmated. As the randomzaton procedure s dentcal between the two experments, 16 observatons could be used and were found suffcent to establsh boequvalence. To avod large subject numbers for practcal, economcal and ethcal reasons, the most approprate technque forfurosemde would be to use a stable sotope-labelled nternal standard. Ths technque totally elmnates ntrasubject varablty and substantally reduces the number of subjects requred [21]. In concluson, ntrasubject varablty has been shown to be a confoundng factor n boavalablty studes of furosemde based on a lmted number of subjects. In general, ntrasubject varablty can nduce dfferent effects n the analyss of boavalablty studes. Actual dfferences may ether be masked or amplfed. False dfferences can also be ntroduced. Ths should be kept n mnd when desgnng and evaluatng boavalablty studes. As ponted out by Jack et al. [22], the clncal mplcatons of varablty n drug dsposton should not be overemphazsed. Many drugs show flat dose- (concentraton)-response curves and dose ttraton s a ratonal approach to lmt the effects of nterndvdual varaton. Intrandvdual varablty, however, can be more dffcult to cope wth. Such varatons have defnte clncal mplcatons for drugs wth a narrow therapeutc range. Acknowledgements. We thank Mss. L.Ekman and B.Ask for ther excellent techncal assstance. Our specal thanks are due to Drs. B. E. Rodda and P.B. Huber for ther valuable advce about the statstcal treatment of the data. References 1. TyrerJH, SutherlandJM, HooperWD (1970) Outbrake of antconvulsant ntoxcaton n an Australan cty. Br Med J 4: Lnderbaum V, Mellow HM, Blackstone MD, Butter VP (1971) Varaton n bologcal avalablty of dgoxn from four preparatons. N Engl J Med 285: Department of Health Educaton and Welfare, Food and Drug Admnstraton (1977) Drug products. Boequvalence requrements and n-vvo boavalablty procedures. Fed Reg, Part III 42: Natonal Board of Health and Welfare (Sweden). Appendx to the Code of Statutes (1980) Regstraton of pharmaceutcal specaltes. Instructons for submsson of applcatons (SOSFS (M) 90: WestlakeWJ (1973) Dosage form and boavalablty. In: SwarbrckJ (ed) Current concepts n the pharmaceutcal scence. Lea and Febger, Phladelpha Dagrosa EE, Hajdu P, Heptner W, Rupp W (1981) The role of ntrasubject varatons n boavalablty studes. Cln Pharmacol Ther 29: Hammarlund MM, Paalzow LK, Odlnd B (1984) Pharmacoknetcs of furosemde n man after ntravenous and oral admnstraton. Applcaton of moment analyss. Eur J Cln Pharmacol 26: Cutler DJ (1978) Theory of the mean absorpton tme, an adjunct to conventonal boavalablty studes. J Pharm Pharmacol 30: Yamaoka K, Nakagawa T, Uno T (1978) Statstcal moments n pharmacoknetcs. J Pharmacoknet Bopharm 6: Regelman S, Coller P (1980) The applcaton of statstcal moment theory to the evaluaton of n vvo dssoluton tme and absorpton tme. J Pharmacoknet Bopharm 8: Westlake WJ (1976) Symmetrcal confdence ntervals for boequvalence trals. Bometrcs 32: Spret A, Beler D (1978) Table to facltate determnaton of symmetrcal confdence ntervals n boavalablty trals wth Westlake's method. Eur J Drug Metab Pharmacoknet 2: Rodda BE, Davs RL (1980) Determnng the probablty of an mportant dfference n boavalablty. Cln Pharmacol Ther 28: Benet LZ (1979) Pharmacoknetcs/pharmacodynamcs of furosemde n man: a revew. J Pharmacoknet Bopharm 7: Cutler RE, Blar AD (1979) Clncal pharmacoknetcs of furosemde. Cln Pharmacoknet 4: Smth DE, Ln ET, Benet LZ (1980) Absorpton and dsposton of furosemde n healthy volunteers measured wth a metabolte-specfc assay. Drug Metab Dsp 8: Waller ES, Hamlton SF, MassarellaJW, SharanevychMA, Smth RV, Yaktan G J, Doluso JT (1982) Dsposton and absolute boavalablty of furosemde n healthy males. J Pharm Sc 71 : 1105-I Brazzell RK, Kaplan SA (1983) Factors affectng the accuracy of estmated mean absorpton tmes and mean dssoluton tmes. J Pharm Sc 72: Prasad VK, Rapaka RS, Knght PW, Cabana BE (1982) Dssoluton medum - a crtcal parameter to dentfy boavalablty problems of furosemde tablets. Int J Pharm 11: Nmmo WS (1976) Drugs, dsease and altered gastrc emptyng. Cln Pharmacoknet 1: Heck H d'a, Butrll SE, Flynn NW, Dryer RL, Anbar M, Carns T, Dghe S, Cabana BE (1979) Boavalablty of mpramne tablets relatve to a stable sotope-labelled nternal standard: ncreasng the power of boavalablty tests. J Pharmacoknet Bopharm 7: Jack DB, Wlkns MR, Kendall, Hall PE (1983) Varablty of plasma drug concentratons: some boservatons. Eur J Cln Pharmacol 25: Receved: June 9, 1984 accepted: August 3t, 1984 Dr. Anders Grahntn Secton of Pharmacoknetcs Pharmacotherapeutc Dvson Department of Drugs Natonal Board of Health and Welfare Box 607 S Uppsala Sweden