- Email: [email protected]
P169 characterisation of central and peripheral tissue distribution of the angiotensin II antagonist losartan and its active metabolite EXP 3174 in the rat
Posters / European Journal of Pharmaceutical Sciences 2 (19941 117-194 P169 CHARACTERISATION OF CENTRAL AND PERIPHERALTISSUE DISTRIBUTION OF THE ANGIOTENSlN II ANTAGONIST LOSARTAN AND ITS ACTIVE METABOUTE EXP 3174 IN THE RAT A. Soldner, H. Spahn.Langguth, E. MutscNer Department of Pharmacology, Johann Wolfgang Goethe-University, 60439 Frankfurt, Germany
Lesartan is a pofent, ~ active, nonbaptiderg~c ~ antagonist of Arlgioter~in It (A II) auMype I (AT1) r~eptors wltich h ~ ~ o , ~ to effeotively ~ breed pressure up to 24 hours after desiug Imd to exert a beneflclat effact on the regression of ves¢4Jlsrh y p e ~ er~onlated with hypedenaion Results from e study oll the melabotism of Lo~rtan In rat, monkey and human liver slice= (1) indicated that the prolonged dundk~ Of A II receptor aofagonlsm by Lo~d~an is mainly due to ample bictrartsformatk~ to carboxytic acid metaheiles which show idgnitieant A II bionldng actMty in contrast to glucuronic acid conjugates being much less active then the parent ~¢rlpormd. The major esrboxylic acid metabotite of Lesartan in rat= and men (EXP 31741 w u de~ribad to be more potent and Iong-actiug than the panmt compound itoeif (2). So far, tissue di=tdbution of Lesartan has been analyzed only alter application and measurement of the total activity of the radictahetied drug lacking the ability to diacdminate between the parent drug and the active metabbilte Aim. Thus, the aim or the present study was to determine the tissue and body fluid distributidn of Lesadan as well as its active mstabolite EXP 3174 in the rat following p o application of Lesartan (10 mg/kg) Furthermore, it was of padicular interest to cladfy whether Lesartan is able to cross the blood-brain barrier Method. The study was performed with rnak~W,~tor rats fasted ovemlgnt (n = 4, n : 2 for c~nlrot animals) w~ich received e single dose of 10 mg~g Lo6arton p.o., dissolved in tap water (5 mg/ml) For the analysis Of liver, lung, kidneys, spleen, head, brain, proximal and distal small intestine, plasma and whole Mood, the rats were anaesthesized with diethyl ether and, after blood was withdrawn by heart puncture, immediately dissected. The respective hssues were weighed and stored at. 80 "C until HPLC analysis. The chromatographic separation was p~/ormed on an ULTREMEX CN column, 3 lam, with 0075M phosphate buffer/H3CCNKHF 68/29/3 (v/v), adjusted to pH 3, as mobile phase. The tissues were homogenized in purified water (2 fold the weight of 1issue) with an Ultra Turrax. The homogenate was acidified with pheaphod¢ acid 85 % to pH 2 - 3 and sonicated. An aliquot of 250 id was mixed with 250 ~dof acofonitrite containing 2 pg/ml I.-158,854 as internal standard, vortexed and centrifuged; 100 ul of the supematant were injected into the HPLC system. An aliquot of the heparinized brand Was centrituged to yield plasma for further HPLC analysis. For the drug determination in wtlole blood, another aliquot was frozen at - 80 *C to destroy the bk~d cell membranes Ixior to further sample treatment. Blood and plasma were acidified to pH 2.5 and extracted with mathyt-t,-butyl ether (MTBE) and washed with n-hexane pr/or to HPLC analysis For the ana/ysls of b~iary excr~on, the rats were anaesthet~ed and bile-duct cannulated The bile was acidified, centrifuged and the supemstant extracted with MTSE and washed with nhexane prior to HPLC For the analysis of liquor cerebrospinalis, the rats were anaesthes~ed and liquor was withdrawn from the foremenmagnumvia punofure. The analysis warsperformed as described for pleema. Results. After oral administration peak levels appealed in most tissues within 45 to 60 minutes The highest concentrations of Losarton and EXP 3174 were found in liver, kidneys and small intestine. Within the find hour after dosing appr~ 5 % of the dOSewere deta~ed in the liver;, the ratio of Losartan to EXP 3174 was 10 : 1 At that time the kidneys contatned only Loesrtan tapir'. 0.1% of the dose), but no metabolite. SO far, neither in brain tissue nor in liquor ceretxospthalls Lesartan and EXP 3174 were detected. (1) Steams R A. st el.: Dug Metabolism and Dlsposlticn 1992. 20, 2 : 281 - 287 (2) Wong PC. et al: J Pharm Exp Therap 1990, 255,1: 21t-217
P171 THE EFFECTS OF SOME PENETRATION ENHANCERSON THE IN VITRO DIFFUSION OF THYROTROPttlN RELEASINGHORMONEACROSSPORCINE BUCCALMUCOSA K.Vyasl, I.W. Kellawayl, A.C. Harm2, A. Dennis3 1 Welsh School of Pharmacy, Cardiff, CF1 3XF, U.K. 2 SEM unit, Prediofc= Sder~es, UWCC, CaP'If, CFI 1SS, U.K. 3 Intemati~ R e ~ and Development Group, B~,tol-ldyers Squibb, Moreton, Wirrtd, L45 lOW, U.K.
161
P170 DICLOFENACI CODEIN PHOSPHATECOMBINATION: RELATIVE BIOAVAILABIUTY OF SUPPOSITORIES AS COMPAREDTO RLM-COATEOTABLETS A. Hansesl, H. Spahn-Langgutht, F. Meiss2, E. Mutschler 1 1 Department of Pharmacokxjy, Johann Wolfgang Goethe-University,60439 Frankfurt, Germany 2 Ciba Geigy GmbH, Medical Depaitmant, 60528 Frankfuft, Germany Combinations of opioid analgesics and non-steroidal anti-inflammatory drugs are widely used in the treatment of moderate and severe pain By addition of codeine phosphate to the non-opioid analgesic diclofenec, analgesic efficacy can be intensified Because oral administration is not possible in several cases, e g in the presence of severe nausea or vomiting, a rectal administration form was developed in addition Thus, the aim of the present study was to investigate the relative bioavailability of suppositories with a combination of 50 mg diclofenac and 50 mg codeine phosphate as compared to film-coated tablets of the same composition (Combaren®). Methods: The study was performed in an open, randomized 2-pedod-cross-ovPr-design (single dose) with 12 healthy, male volunteers (21 to 40 years of age), who received a combination of 50 mg diclofenac and 50 mg codeine phosphate either rectally as suppository or orally as film-coated tablet (reference) Blood samples were collected prior to dosing and in appropriate intervals up to 24 h thereafter. After liquid-liquid extraction from plasma both drugs were determined with sensitive and specific HPLC methods using UVdetection for diclofenac and fluorescence detection for codeine, respectively. The limit of detection was 5 ng/ml for both drugs. Diclofenac; The chromatographic system included a Spherisorb ODS lI 3pro column as stationary and a mixture of 0,05M potassium phosphate buffer pH 3.1 I acetonitrile / tetrahydrofurane (65/30/5; v/v) as mobile phase UV-detection was performed at 282 n m 4"-Methoxydic/ofenae sewed as internal standard Codeine: As stationary phase a Zorbax CN column was used, the mobile phase consisted of a mixture of 0 0 1 M potassium phosphate buffer pH 4 9 and acetonitrile (83117; v/v), containing 5 m M sodium decane sulfate as an ion-pairing agent After excitation at 285 nm, fluorescence detection was performed at 365 n m The internal standard was ethylmorphine. Results: The main target parameter AUC0.= was not significantly different in both treatment groups under the conditions described (tested on a significance level of c¢ = 0.05) The geometric mean of the relative bioavailability of the suppositories was 110.8% (95% confidence interval: 99.8% - 1 2 3 0 % ) for diclofenac and 109.8% (95% confidence interval: 90,1% - 133.9%) for codeine. Referring to the pharmacokinetic parameters Cr.ax and tm=x typical differences between oral and rectal application forms were observed. For the suppositories, diclofenac and codeine average peak plasma concentrations were only half as high as for the tablets, whereas tbe respective tmag values were doubled. Hence, the extent of diclofenac and codeine absorption was similar for both administration routes, but the rate of drug input was lower for the suppositories.
P172 INTERSPEClES SCALING OF PHARMACOKINETICPARAMETERSOF MEPINDOLOL S. Wundschock-Sanderl, M. H i k e 1 , K.-H. Beyer2 I Institute of Pharmacddnetica, Sehenng AG, 13353 Berl~, Germany 2 Faculty of Pharmacy, Free University of Bedin, 14195 Berlin, Germany
e.ahaneers: sodium taurodihydrofusidate (STDHF), didecanoyl pnospbatidylcholine (DDWS) and lysophospbatidylcholine (LFC).
Mepindolol (Corindolan ~ ) is a non cardiosc, lective I]-blocking agent used pharmacotherapeutically in the low 2.5 - 10 mg dose range for treatment of hypertension, angina peetoris and hyperkinetic heart syndrome. The pharmacokinetic of 14C-labelled mepiodolol was studied in rats, monkeys and dogs after both i.w and i.g. administration of approximately 0.4 mg/kg. Apart from plasma level profiles routes and rates of excretion were studied by LSC and HPLC radiochromatography. Pharrnacokinetic parameters were calculated by Top Fit 2,0, lmerspeeies extrapolation was performed by allometric sealing. The pharmacokinetic parameters of mepindolol obtained after i,v. dosing in the three animal species are given in table l. Enantioselective pharmacokinetics were not observed,
The peptide studied was thyrotrophin releasing hormone (TRIO as it has been
Table I:
Bucc~ .d~ugdelive.ry is advantageous as the buccal site is easily accessible, has a gooo ¢rooa supply, me arng is absorbed directly into the systemic circulation avoiding hepalac first pass metabolism and avoids degradation by gastro intestinal enzymes (1). Therefore, the bnccal route of administration offers a useful alternative to the parenterni route for the delivery of proteins and l?eptides. The aim of the study was to set up an in vitro model to assess the zeasibility of buccal absorption and to evaluate the effects of three penetration
shown, in vivo, to produce a clinical effect on buccal administration (2). Porcine buceal mueosa was selected as it possesses structural similarities to human buccal mucosa and it is readily available O). The tissue was mounted in a Franz diffusion cell and the diffusion of radiolabelled TRH monitored over 8 hr at 37 *C in buffer pH 7.4. TRH was found to traverse the mucosa with an apparent permeability coefficient of 2.03 x 10-7 (± 0.46 SEM) em/s. The tissue was found to be viable for upto 8 hr under experimental conditions using ATP level detection, electron microscopy and electrical resistance measurements. The l~:~ancement Ratios (ER) for the permeation of TRH (n=6) in the presence of 0.5 % w/v of LI'-C, DDPC and STDI..]Fwere found to be 2.37, 3.25 and 7.1 respectively. The mechanism by which increased diffusion occurs is probably due to the reduced membrane microviscosity due to solubllisation of membrune lipids by these penetration enimacers (4). Tbls may also increase the paracellular transport of TRI"Iacross the tissue. R~ereaeas (1) llarris, D. and Robinson, J.IL, J.Pharm.Sci. 81:1-10 (1992). (2) Anders, R., Merlde, H. P., Sehurr, W. and Zeigler, R., J.Pharm.Sci. 72: 1481-1483 (19831. (3) Squier, C.A.und Ilall, B.IL, J.InvestDerm. 84: 176- 179 (1985). (4) August, B. 3. and Rogers, N. J., lnt/.Pharm. 53:227-235 (19891.
Pharmacokinetic parameters of nte findolol obtained parameter rat monkey MRT [hi 0.57 I.I V . [ll 1.3 44.2 CI,., [ml/min I 37.8 658
after i.v. a, plication dog man 1.8 5.03 139 315 1323 1043
MRT-mean residence time, Vss- volume of distribution in steady state, Citet - total clearance By means of interspecies scaling using body weight (B [kg]) as a correlation factor total clearance, volume of distribution and mean residence time could be modelled. Except for the clearance an extrapolation of pharmacokinetic data obtained in man in an earlier study showed a very satisfying prognostic value of the approach used. Clearance in man was considerably less than predicted from the other species (table 2).
Table 2:
Equation ; of regression of interspecies correlation .parameter allometric equation r2 MRT MRT - 0.80. B0.37 0.92 V~ V~ - 6.8 • B l 0.97 Clm+ Clm; - 140, B T M 0.84 If the maximum lifespan potential was taken into consideration a good correlation was also obtained for the clearance as could be seen in the following equation. I CLml- 643950. B 1.13 I In summary pharmacokinetic parameters of mepindolol could be scaled for several animal species and man using body weight and maximum lifetime potential. A clearance correlation was achieved if maximum lifespan potential was taken into consideration. This interspecies correlation showed that allometric extrapolation can be a predictive tool for pharmacokiuetic parameters.
Lesartan is a pofent, ~ active, nonbaptiderg~c ~ antagonist of Arlgioter~in It (A II) auMype I (AT1) r~eptors wltich h ~ ~ o , ~ to effeotively ~ breed pressure up to 24 hours after desiug Imd to exert a beneflclat effact on the regression of ves¢4Jlsrh y p e ~ er~onlated with hypedenaion Results from e study oll the melabotism of Lo~rtan In rat, monkey and human liver slice= (1) indicated that the prolonged dundk~ Of A II receptor aofagonlsm by Lo~d~an is mainly due to ample bictrartsformatk~ to carboxytic acid metaheiles which show idgnitieant A II bionldng actMty in contrast to glucuronic acid conjugates being much less active then the parent ~¢rlpormd. The major esrboxylic acid metabotite of Lesartan in rat= and men (EXP 31741 w u de~ribad to be more potent and Iong-actiug than the panmt compound itoeif (2). So far, tissue di=tdbution of Lesartan has been analyzed only alter application and measurement of the total activity of the radictahetied drug lacking the ability to diacdminate between the parent drug and the active metabbilte Aim. Thus, the aim or the present study was to determine the tissue and body fluid distributidn of Lesadan as well as its active mstabolite EXP 3174 in the rat following p o application of Lesartan (10 mg/kg) Furthermore, it was of padicular interest to cladfy whether Lesartan is able to cross the blood-brain barrier Method. The study was performed with rnak~W,~tor rats fasted ovemlgnt (n = 4, n : 2 for c~nlrot animals) w~ich received e single dose of 10 mg~g Lo6arton p.o., dissolved in tap water (5 mg/ml) For the analysis Of liver, lung, kidneys, spleen, head, brain, proximal and distal small intestine, plasma and whole Mood, the rats were anaesthesized with diethyl ether and, after blood was withdrawn by heart puncture, immediately dissected. The respective hssues were weighed and stored at. 80 "C until HPLC analysis. The chromatographic separation was p~/ormed on an ULTREMEX CN column, 3 lam, with 0075M phosphate buffer/H3CCNKHF 68/29/3 (v/v), adjusted to pH 3, as mobile phase. The tissues were homogenized in purified water (2 fold the weight of 1issue) with an Ultra Turrax. The homogenate was acidified with pheaphod¢ acid 85 % to pH 2 - 3 and sonicated. An aliquot of 250 id was mixed with 250 ~dof acofonitrite containing 2 pg/ml I.-158,854 as internal standard, vortexed and centrifuged; 100 ul of the supematant were injected into the HPLC system. An aliquot of the heparinized brand Was centrituged to yield plasma for further HPLC analysis. For the drug determination in wtlole blood, another aliquot was frozen at - 80 *C to destroy the bk~d cell membranes Ixior to further sample treatment. Blood and plasma were acidified to pH 2.5 and extracted with mathyt-t,-butyl ether (MTBE) and washed with n-hexane pr/or to HPLC analysis For the ana/ysls of b~iary excr~on, the rats were anaesthet~ed and bile-duct cannulated The bile was acidified, centrifuged and the supemstant extracted with MTSE and washed with nhexane prior to HPLC For the analysis of liquor cerebrospinalis, the rats were anaesthes~ed and liquor was withdrawn from the foremenmagnumvia punofure. The analysis warsperformed as described for pleema. Results. After oral administration peak levels appealed in most tissues within 45 to 60 minutes The highest concentrations of Losarton and EXP 3174 were found in liver, kidneys and small intestine. Within the find hour after dosing appr~ 5 % of the dOSewere deta~ed in the liver;, the ratio of Losartan to EXP 3174 was 10 : 1 At that time the kidneys contatned only Loesrtan tapir'. 0.1% of the dose), but no metabolite. SO far, neither in brain tissue nor in liquor ceretxospthalls Lesartan and EXP 3174 were detected. (1) Steams R A. st el.: Dug Metabolism and Dlsposlticn 1992. 20, 2 : 281 - 287 (2) Wong PC. et al: J Pharm Exp Therap 1990, 255,1: 21t-217
P171 THE EFFECTS OF SOME PENETRATION ENHANCERSON THE IN VITRO DIFFUSION OF THYROTROPttlN RELEASINGHORMONEACROSSPORCINE BUCCALMUCOSA K.Vyasl, I.W. Kellawayl, A.C. Harm2, A. Dennis3 1 Welsh School of Pharmacy, Cardiff, CF1 3XF, U.K. 2 SEM unit, Prediofc= Sder~es, UWCC, CaP'If, CFI 1SS, U.K. 3 Intemati~ R e ~ and Development Group, B~,tol-ldyers Squibb, Moreton, Wirrtd, L45 lOW, U.K.
161
P170 DICLOFENACI CODEIN PHOSPHATECOMBINATION: RELATIVE BIOAVAILABIUTY OF SUPPOSITORIES AS COMPAREDTO RLM-COATEOTABLETS A. Hansesl, H. Spahn-Langgutht, F. Meiss2, E. Mutschler 1 1 Department of Pharmacokxjy, Johann Wolfgang Goethe-University,60439 Frankfurt, Germany 2 Ciba Geigy GmbH, Medical Depaitmant, 60528 Frankfuft, Germany Combinations of opioid analgesics and non-steroidal anti-inflammatory drugs are widely used in the treatment of moderate and severe pain By addition of codeine phosphate to the non-opioid analgesic diclofenec, analgesic efficacy can be intensified Because oral administration is not possible in several cases, e g in the presence of severe nausea or vomiting, a rectal administration form was developed in addition Thus, the aim of the present study was to investigate the relative bioavailability of suppositories with a combination of 50 mg diclofenac and 50 mg codeine phosphate as compared to film-coated tablets of the same composition (Combaren®). Methods: The study was performed in an open, randomized 2-pedod-cross-ovPr-design (single dose) with 12 healthy, male volunteers (21 to 40 years of age), who received a combination of 50 mg diclofenac and 50 mg codeine phosphate either rectally as suppository or orally as film-coated tablet (reference) Blood samples were collected prior to dosing and in appropriate intervals up to 24 h thereafter. After liquid-liquid extraction from plasma both drugs were determined with sensitive and specific HPLC methods using UVdetection for diclofenac and fluorescence detection for codeine, respectively. The limit of detection was 5 ng/ml for both drugs. Diclofenac; The chromatographic system included a Spherisorb ODS lI 3pro column as stationary and a mixture of 0,05M potassium phosphate buffer pH 3.1 I acetonitrile / tetrahydrofurane (65/30/5; v/v) as mobile phase UV-detection was performed at 282 n m 4"-Methoxydic/ofenae sewed as internal standard Codeine: As stationary phase a Zorbax CN column was used, the mobile phase consisted of a mixture of 0 0 1 M potassium phosphate buffer pH 4 9 and acetonitrile (83117; v/v), containing 5 m M sodium decane sulfate as an ion-pairing agent After excitation at 285 nm, fluorescence detection was performed at 365 n m The internal standard was ethylmorphine. Results: The main target parameter AUC0.= was not significantly different in both treatment groups under the conditions described (tested on a significance level of c¢ = 0.05) The geometric mean of the relative bioavailability of the suppositories was 110.8% (95% confidence interval: 99.8% - 1 2 3 0 % ) for diclofenac and 109.8% (95% confidence interval: 90,1% - 133.9%) for codeine. Referring to the pharmacokinetic parameters Cr.ax and tm=x typical differences between oral and rectal application forms were observed. For the suppositories, diclofenac and codeine average peak plasma concentrations were only half as high as for the tablets, whereas tbe respective tmag values were doubled. Hence, the extent of diclofenac and codeine absorption was similar for both administration routes, but the rate of drug input was lower for the suppositories.
P172 INTERSPEClES SCALING OF PHARMACOKINETICPARAMETERSOF MEPINDOLOL S. Wundschock-Sanderl, M. H i k e 1 , K.-H. Beyer2 I Institute of Pharmacddnetica, Sehenng AG, 13353 Berl~, Germany 2 Faculty of Pharmacy, Free University of Bedin, 14195 Berlin, Germany
e.ahaneers: sodium taurodihydrofusidate (STDHF), didecanoyl pnospbatidylcholine (DDWS) and lysophospbatidylcholine (LFC).
Mepindolol (Corindolan ~ ) is a non cardiosc, lective I]-blocking agent used pharmacotherapeutically in the low 2.5 - 10 mg dose range for treatment of hypertension, angina peetoris and hyperkinetic heart syndrome. The pharmacokinetic of 14C-labelled mepiodolol was studied in rats, monkeys and dogs after both i.w and i.g. administration of approximately 0.4 mg/kg. Apart from plasma level profiles routes and rates of excretion were studied by LSC and HPLC radiochromatography. Pharrnacokinetic parameters were calculated by Top Fit 2,0, lmerspeeies extrapolation was performed by allometric sealing. The pharmacokinetic parameters of mepindolol obtained after i,v. dosing in the three animal species are given in table l. Enantioselective pharmacokinetics were not observed,
The peptide studied was thyrotrophin releasing hormone (TRIO as it has been
Table I:
Bucc~ .d~ugdelive.ry is advantageous as the buccal site is easily accessible, has a gooo ¢rooa supply, me arng is absorbed directly into the systemic circulation avoiding hepalac first pass metabolism and avoids degradation by gastro intestinal enzymes (1). Therefore, the bnccal route of administration offers a useful alternative to the parenterni route for the delivery of proteins and l?eptides. The aim of the study was to set up an in vitro model to assess the zeasibility of buccal absorption and to evaluate the effects of three penetration
shown, in vivo, to produce a clinical effect on buccal administration (2). Porcine buceal mueosa was selected as it possesses structural similarities to human buccal mucosa and it is readily available O). The tissue was mounted in a Franz diffusion cell and the diffusion of radiolabelled TRH monitored over 8 hr at 37 *C in buffer pH 7.4. TRH was found to traverse the mucosa with an apparent permeability coefficient of 2.03 x 10-7 (± 0.46 SEM) em/s. The tissue was found to be viable for upto 8 hr under experimental conditions using ATP level detection, electron microscopy and electrical resistance measurements. The l~:~ancement Ratios (ER) for the permeation of TRH (n=6) in the presence of 0.5 % w/v of LI'-C, DDPC and STDI..]Fwere found to be 2.37, 3.25 and 7.1 respectively. The mechanism by which increased diffusion occurs is probably due to the reduced membrane microviscosity due to solubllisation of membrune lipids by these penetration enimacers (4). Tbls may also increase the paracellular transport of TRI"Iacross the tissue. R~ereaeas (1) llarris, D. and Robinson, J.IL, J.Pharm.Sci. 81:1-10 (1992). (2) Anders, R., Merlde, H. P., Sehurr, W. and Zeigler, R., J.Pharm.Sci. 72: 1481-1483 (19831. (3) Squier, C.A.und Ilall, B.IL, J.InvestDerm. 84: 176- 179 (1985). (4) August, B. 3. and Rogers, N. J., lnt/.Pharm. 53:227-235 (19891.
Pharmacokinetic parameters of nte findolol obtained parameter rat monkey MRT [hi 0.57 I.I V . [ll 1.3 44.2 CI,., [ml/min I 37.8 658
after i.v. a, plication dog man 1.8 5.03 139 315 1323 1043
MRT-mean residence time, Vss- volume of distribution in steady state, Citet - total clearance By means of interspecies scaling using body weight (B [kg]) as a correlation factor total clearance, volume of distribution and mean residence time could be modelled. Except for the clearance an extrapolation of pharmacokinetic data obtained in man in an earlier study showed a very satisfying prognostic value of the approach used. Clearance in man was considerably less than predicted from the other species (table 2).
Table 2:
Equation ; of regression of interspecies correlation .parameter allometric equation r2 MRT MRT - 0.80. B0.37 0.92 V~ V~ - 6.8 • B l 0.97 Clm+ Clm; - 140, B T M 0.84 If the maximum lifespan potential was taken into consideration a good correlation was also obtained for the clearance as could be seen in the following equation. I CLml- 643950. B 1.13 I In summary pharmacokinetic parameters of mepindolol could be scaled for several animal species and man using body weight and maximum lifetime potential. A clearance correlation was achieved if maximum lifespan potential was taken into consideration. This interspecies correlation showed that allometric extrapolation can be a predictive tool for pharmacokiuetic parameters.