Deutsche Pharmakologische Gesellschaft Abstracts of the 19. Spring Meeting March 14 -17, 1978, Mainz Springer-Verlag Berlin Heidelberg GmbH ISBN 978-3-662-38666-8 ISBN 978-3-662-39532-5 (eBook) DOI 10.1007/978-3-662-39532-5 Softcoverreprint ofthe bardeover 1st edition 1978 III 19th Spring Meeting Deutsche Pharmakologische Gesellschaft Mainz, March 14 - 17, 1978 Abstract Numbers 1. Absorption, Distribution, Pharmacokinetics 1 - 11 2. Biochemical Pharmacology, Drug Metabolism 12 - 50 3. Toxicology 51 - 92 4. Cyclic Nucleotides 93 - 103 5. Prostaglandins 104 - 112 6. Heart 113 - 143 7. Circulation 144 - 151 8. Experimental Hypertension 152 - 162 9. Renin, Angiotensin 163 - 165 10. Renal Pharmacology 166 - 171 11. Endocrine Pharmacology 172 - 180 12. Gastroenterology 181 - 185 13. Immunopharmacology, Antiinflammatory Drugs 186 - 191 14. Adrenergic Mechanisms 192 - 213 15. Cholinergic Mechanisms 214 - 218 16. Central Nervous System 219 - 248 17. Clinical Pharmacology and Toxicology 249 - 267 V AUTHOR-INDEX Figures = Abstract Numbers Abel, J. 63 Dietz, J. 96 Gramsch, Ch. 241 Aenstoots, F. 180 Dietz, R. 163 Greeff, K. 113 Ahnfe lt-R~nne, I. 105 Dittmar, W. 24 Greeff, U. 71 Aichinger, G. 32 Döderlein, P. 117 Grei ner, B. 239 Alsen, C. 56 Dost, E. 72 Greven, J. 168 Ammon , H. P. T. 175 Drommer, W. 74 Grill, H. 19 Anda, L.P. 68 Dross, K. 39 Grobecker, H. 195 Anhut, H. 108 Dünges, W. 12 Grötsch, H. 195 Appel, E. 195 Gross, F. 163 Appel, K.E. 80 Ebner, F. 124 Groß-Selbeck, E. 65 Arendes, J. 25 Eckard, R. 53 Grundmann, E. 70 Eder, E. 83 Güttler, K. 136 Bader, H. 152 Egger, H. 59 Gugler, R. 255 Bäßmann, H. 22 Ehlert, U. 50 Gundert-Remy, u. 11 Barnikol, W.K.R. 261 Ehrenthal, W. 52 Bartsch, W. 154 Ehrlich, K. 2 Haap, K. 119 Bass, R. 58 Eibs, H.-G. 21 Haarmann, I. 240 Baumann, J. 104 Eichelbaum, M. 256 Haass, A. 254 Becher, R. 114 El Sayed, M.A. 225 Hackl, J.M. 194 Becker, G. 1 Eltze, M. 204 Haeger, G. 135 Beckmann, J. 177 Endell,W. 74 Hänsel, R. 104 Bellemann, P. 47 Ening, R. 53 Haeusler, G. 208 Benthe, H.F. 29 Ening, W. 53 Hafner, D. 113 Bentley, P. 26 Erdmann, E. 134 Halbach, S. 66 Bergholz, H. 7 Erttmann, R.R. 7 Halbhübner, K. 234 Bernasconi, R. 230 Eyer, P. 48 Hamacher, J. 55 Bertram, H. P. 8 Hammerle, A.F. 194 Beubler, E. 185 Fassold, E. 129 Hampel, H. 19 Beyhl, F.E. 35 Fehske, K.J. 13 Haselbach, J. 78 Bhattacharya, s. 56 Feldtrauer, J.-J. 231 Havemann, U. 245 Binder, J.P. 139 Felgenträger; J. 133 Hedwa 11 , P . R. 167 Bittiger, H. 215 Felix, W. 213 Heimann, G. 257 Bläsig, J. 244 Fernandes, M. 247 Heinemeyer, G. 30 Block, W. 27 Fetz, H. 88 Heintze, K. 182 Bock, K. W. 46 Fichtl, B. 6 Heinz, G. 232 Bodem, G. 262 Fiechter, A. 15 Hellwich, M. 96 Bönisch, H. 198 Fiedler, V.B. 143 Hempel, V. 263 Böttcher, J. 22 Filser, J.G. 85 Hengstmann, J.H. 252 Bolt, H.M. 85 Finch, S. 42 Henning, H. 3 Bolte, H.-D. 116 Fingerle, H. 151 Henschler, D. 88 Borchard, U. 113 Fischer, C. 259 Henseling, M. 197 Bossert, F. 141 Fischer, Ch. 172 Hering, E. 220 Brantl , V. 240 Fischer, H. 61 Herken, R. 20 Braun, R. 24 Fleischmann, R. 60 Hertting, G. 200 Breyer-Pfaff, U. 253 Flockerzi, V. 99 Herz, A. 244 Bridges, J.W. 31 Förster, B. 168 Hesse, S. 91 Brinkmann, H.-M. 10 Förster, H.-J. 40 Heucke, U. 222 Brinkschulte, M. 253 Forth, W. 3 Hildebrandt, A.G. 30 Brodde, 0.-E. 100 Freundt, K.J. 76 Hlavica, P. 32 von Bruchhausen, F. 104 Frey, H.-H. 224 Höfeler, H. 220 Brücke, Th. 194 Fricke, U. 137 Höfling, B. 116 Brückner, R. 122 Frickhofen, N. 189 Höllt, V. 241 ten Bruggencate, G. 219 Frimmer, M. 69 Hörtnagl, H. 194 Brune, K. 109 Fröscher, W. 256 Hofmann, F. 99 Bruns, W. 23 Fuhrmann, G.F. 15 Hofrichter, G. 19 Büch, H.P. 50 Fuxe, K. 237 Hollatz, R. 51 Burger, A. 192 Holze, S. 176 Busse, F. 132 Gabard, B. 67 Holzer, P. 227 Busse, W.D. 190 de 1a Ga 1a , E. 172 Honec ker, H. 249 Gamse, R. 227 Hoos, W.R. 88 Cambri dge, D. 206 Ganten, D. 164 Hropot, M. 169 Castritius, M. 192 Ganten, U. 165 Huber, E. 46 Christ, W. 205 Gassel, W.-D. 24 Huck, S. 221 Classen, H.G. 127 Gastauer, R. 183 Huljus, R. 17 Coell e, E. F. 238 Gau, W. 190 Hummelt, H. 218 Coper, H. 249 Gebefügi, I. 90 Huß, R. 211 Cremer, H. 238 Gerlaff, J. 262 Criscione, L. 167 Gidion, U. 16 Iven, H. 128 Czempiel, W. 57 Gladtke, E. 251 Czypionka, M. 262 Glatt, H.R. 26 Jacob, R. 127 Glatt, M. 109 Jacob-Müll er, U. 21 Dallmeier, E. 86 Glossmann, H. 98 Jähnchen, E. 258 Damani, L.A. 38 Godbillon, J. 258 Jahns, I. 253 Damerau, B. 188 Goedert, M. 193 Jakobs, K.H. 203 Damm, K.H. 7 Goerg, K.J. 4 Jarosch, U. 199 Darda, S. 40 Görler, K. 49 Jennewein, H.M. 218 Davey, M.J. 206 Görlitz, B.-D. 246 Jerzabek, G. 173 Deckers-Schmelzle, B. 92 Göthert, M. 201 Jess, H.H. 10 Delini-Stula, A. 226 GogoHtk, G. 221 Jindra, R. 221 Dieter, H. 63 Goldberg, H.-J. 177 Johnson, A.K. 164 Di ether, K. 261 Golenhofen, K. 144 Jonen, H.G. 41 Dietl, H. 233 Gorrod, J.W. 38 Joost, H.G. 178 Di etmann, K. 154 Graefe, K.-H. 196 Josting, D. 46 VI Juan, H. 185 Lopez del Pino, V. 44 Porsius, A.J. 156 Jurna, I. 232 Lorenz, J. 60 Porzig, H. 95 Lorenz, W. 250 Poser, S. 266 Käl in, H. 109 Losert, W. 112 Poser, W. 266 Kahl, G.F. 92 Loth, P. 242 Preuner, J. 120 Kahl, R. 33 Lüll mann, H. 132 Prop, G. 162 Kaiser, G. 96 Lüth, J.B. 153 Proppe, D. 135 Ka 1b hen, D.A. 191 Przew~ocki, R. 241 Kal ix, P. 94 Mack, F. 198 Puls, W. 28 Kam, R. 231 Magner, L. 172 Pursche, R. 128 Kampffmeyer, H. 48 Magnussen, M.P. 105 Puurunen, J. 210 Kampmann, E. 128 Mäitre, L. 215 Kappus, H. 37 Malorny, G. 17 Quiring, K. 205 Kasper, W. 258 Mann, J.F.E. 163 Kasperek, K. 68 Mannhold, R. 141 Raberger, G. 139 Kaßpohl, S. 27 Martin, P. 230 Rascher, W. 153 Kather, H. 102 Martorana, P.A. 222 Rauch, C. 186 Kaumann, A.J. 209 Massingham, R. 206 Rauschek, R. 203 Keck, C. 27 Mayer, N. 228 Ravens, U. 120 Kehr, W. 235 McLachlan, J.A. 36 von Rechenberg, W. 173 Keller, B. 196 Meinertz, T. 258 Reichert, D. 87 Kellermann, B. 266 Mennicke, W.H. 49 Reimann, W. 200 Kemper, F.H. 180 Mensing, H.J. 125 Reinhard, M. 207 Keppeler, H. 23 Menzel, H. 63 Reiter, M. 123 Keup, U. 28 Metsä-Ketelä, T. 184 Remmer, H. 78 Keyriläinen, K. 184 Metzler, H. 47 Rempel, P. 147 Kieczka, H. 89 Metzler, M. 36 Richard, J. 258 Kiesel, K. 12 Meyer, B. 136 Rickart, R. 81 Kilbinger, H. 217 Meyer, D.K. 174 Ringsgwandl, G. 213 Kilian, U. 5 Meyer, H. 141 Rinner, I. 97 Klappstein, I. 106 Meywald, K. 168 Rissing, R. 211 Klaus, E. 92 Mezger, M. 91 Roddewig, C. 54 Klaus, W. 136 Mink, K.-0. 158 Rodenkirchen, R. 141 Kl immek, R. 54 von Möllendorff, E. 154 Rösch, I. 86 Klockow, M. 107 Möller, E. 141 Rösen, R. 138 Klotz, U. 259 du Moulin, A. 93 Rohlaff, C. 29 Kluwe, S. 247 Müller, D. 181 Rommelspacher, H. 239 Knepel, W. 174 Müller, G. 267 Roozekrans, N.Th.P. 212 Kobinger, W. 145 Müller, W.E. 14 Roth, B. 251 König, W. 189 Müller, W.E.G. 25 Rothkopf-Ischebeck, M. 110 Köster, U. 263 Muschaweck, R. 169 Ruoff, H. -J • 101 Kohlhardt, M. 119 Mutsch 1e r, E. 169 Kolassa, N. 142 Sandow, J. 173 Kommere ll , B. 102 Nau, H. 59 Saria, A. 228 Korte, B. 163 Nayler, W.G. 129 Schelling, P. 165 Kraas, E. 183 Nell, G. 4 Schenkman, J.B. 37 Kraetz, J. 167 Netter, K.J. 31 Schill inger, E. 112 Krause, H.P. 28 Neudec ker, T. 83 Schirop, Th. 265 Kremer, G. 207 Neugebauer, E. 250 Schleich, I. 149 Kremer, J. 71 Nitz, R.-E. 222 Schlepper, J. 183 Kretzschmar, R. 223 Noack, E. 133 Schliep, H.-J. 158 Kreuser, E.D. 74 Nowak, H. 107 Schlossmann, K. 118 Kreye, V.A.W. 149 Schmassmann, H.U. 60 Krieg, C. 217 Ochs, H.R. 262 Schmidt, G. 147 Krieglstein, J. 220 Oesch, F. 26 Schmidt, M. 153 Kromer, W. 172 Ohnesorge, F.K. 63 Schmidt, W. 9 Krumbiegel, G. 49 Okonek, S. 264 Schmitz, W. 126 Kruse, E. 126 Osborne, H. 243 Schmoldt, A. 29 Kücükhüseyin, C. 121 Osborne, N.N. 238 Schmutzler, W. 186 Kuhn, M. 55 Osswald, H. 166 Schneider, H. 242 Kukovetz, W.R. 129 Osterloh, K. 2 Schneider, H. 15 Kullmann, R. 211 Otten, U. 193 Schneider, M. 95 Kunz, H.W. 80 Ottenwälder, H. 84 Schölkens, B.A. 111 Kurz, H. 6 Schömig, A. 153 Kuschinsky, K. 245 Palm, D. 207 Schönfeld, W. 186 Kussmaul, M. 18 Panten, U. 176 Schönhöfer, P.S. 106 Parantainen, J. 184 Schöning, B. 250 Laib, R.J. 84 Patterson, L. 38 Scho ltho 1t, J. 143 Lambrecht, G. 214 Penin, H. 255 Scholz, H. 134 Laszlo, J. 215 Pentz, R. 79 Schombert, I. 50 Lauterbach, F. 5 Peskar, B.A. 108 Schorscher, E. 158 Legrum, W. 64 Peskar, B.M. 108 Schrör, K. 137 Lembeck, F. 227 Peters, T. 132 Schümann, H.J. 100 Lemmer, B. 199 Petersen, K.-U. 182 Schüppel, R. 22 Lemoine, H. 209 Petzinger, E. 69 Schütte, I. 58 Leng, E. 171 Pfaff, E. 78 Schüttler, J. 252 Lenzen, S. 179 Pfleger, K. 52 Schütz, A. 17 Leyck, S. 76 Pflughaupt, K.W. 254 Schütz, A. 254 Liehn, H. 19 Philipp, G. 134 Schütz, W. 140 Li ndner, E. 195 Phil ippu, A. 233 Schützenberger, W.G. 142 Link, H.J. 138 Pichler, L. 145 Schuh, F.T. 260 Löscher, W. 224 Pieper, B. 5 Schuhmacher, P. 150 Löser, R. 18 Pittner, H. 146 Schulte Hermann, R. . 82 Loew, D. 170 Pl acheta, P. 229 Schultz, J. 93 Loge, 0. 112 Platt, K. 26 Schulz, R. 242 Loos, D. 234 Poblete-Freundt, G. 186 Schulze, G. 248 VII Schunack, W. 102 Steffen, I. 18 Wagner, J. 100 Schuster, J. 205 Steinberg, R. 219 Wal deck, F. 218 Schwabe, U. 103 Steiner, N. 248 Waldmeier, P.C. 231 Schwarz, B. 250 Stepanek, J. 148 Walland, A. 150 Schwarz, L.R. 45 Stier, A. 42 Walter, H. 130 Schwarz, M. 81 Stoeckel, H. 252 Wasmus, A. 106 von Schwarzenfeld, I. 216 Stöcklin, K. 231 Waßermann, K. 211 Schwed itsch, M. 227 Stoll, W. 173 Wassermann, 0. 16 Schwenk, M. 43 Strecker, H. 173 Weber, E. 11 Seeger, R. 62 Strubelt, 0. 73 Weger, N. 54 Seibel, K. 123 Struck, C.J. 98 Weigert, P. 61 Seidel, G. 74 Struyker-Boudier, H. 157 Weithmann, U. 111 Seiler, K.-u. 10 Stumpf, Ch. 221 Welsch, F. 59 Seuter, F. 190 Sweatman, B.C. 31 Wendisch, U. 17 Sewing, K.-Fr. 181 Werner, H.W. 87 Seyfried, C.A. 237 Westermann, E. 210 Tempel, K. 51 el Sherbini-Schepers, M.A. 161 Wever, K. 220 Tertel, R. 205 Siegers, C.-P. 75 Wiebel, F.J. 90 Tesch, H. 189 Sigmund, M. 257 Wiedemann, G. 164 Teschemacher, H. 240 Simon, B. 102 Wiemer, G. 207 Teschendorf, H.J. 223 Simon, W. 164 Wiener, H. 142 Theisohn, M. 257 Singer, E. 229 Wierichs, R. 131 Thoenen, H. 193 Slater, T. 42 de Wildt, D. 156 Thomas, G. 28 Sloos, R. 160 Winterhoff, H. 180 Timmermans, P.B.M.W.M. 159 Smits, J.F. 155 Wolburg, H. 47 Towart, R. 118 Sörgel, F. 169 Wolf, Th. 158 Sontag, K.-H. 238 Tuisl, E. 142 Wolff, Th. 34 Sourgens, H. 180 Wollert, U. 13 Ul brich, B. 57 Specht, W. 4 Worstmann, W. 223 Speer, C. 266 Wüster, M. 242 Valentin, P. 56 Speichermann, N. 99 Wurm, A. 97 Vapaatalo, H. 184 Spielman, W.S. 166 Wurm, G. 104 Verspohl, E.J. 175 Spielmann, H. 20 Vetterlein, F. 147 Spillner, C. 154 Zahn, R.K. 25 Völ pel, M. 73 Sponer, G. 165 Zetl er, G. 128 Vogel, G. 171 Stadler-Wolffersgrün, R. 194 Zettner, B. 133 Vogel, K. 26 Stähle, H. 40 Ziegler, A. 6 Vogt, W. 187 Staib, A.H. 195 Ziegler, A. 121 Vohland, H.-W. 265 Stanek, B. 140 Ziehm, E. 115 Starey, F. 195 Zschocke, R. 19 Starke, K. 202 Wachtel, H. 236 Zumstein, A. 200 Steffen, Ch. 77 Wachter, I. 6 van Zwieten, P.A. 161 R1 3 INTESTINAL ABSORPTICN ClF CXJBALT AND IRJN: INTERACI'ICN SECRETICN OF T!W.LOUS ICNS FROM THE BLOOD INTO THE GI\.STID AND SUBCELLULI\R DISTRIBUI'ICN G. Becker INTESTINAL TRACl' OF RATS H.Henning and W.Forth The absorption kinetic 10 min after administration of 59pe-(FeC13) and 60co-(CoC12) in increasing doses (0,5 - The secretion of thallous ions from the blood into the 1(XX) ng-at metal) in tied off duodenal segments of normal lumen of the stomach, the jejunum and the colon was in and iron-deficient (d) rats shows saturation characteris vestigated in situ on anesthetized rats (urethane, 1.25 tic for both metals. The effect of cobalt on iron absorp gjkg). The method of the pendulum perfusionwas used; a tion was studied in d rats at iron doses of 10 and 200 detailed description of the me~ is given. The movement ng-at iron. When administring 200 ng-at iron the presence of fluid was measured by aid of C-PEG. In the starnach of 108 ng-at cobalt caused a reduction of iron absorption a net secretion of fluid was observed. The fluid volume to 40 percent; excess of cobalt (1080 ng-at) diminished absorbed in the jejunum and in the colon was o.oS and iron absorption to about 9 percent, whereas the uptake of o.o44 ml/cm length respectively. iron into the nrucosa did not differ fran the controls. In an equal anount, however, cobalt (9 ng-atl did not di After the intravenous in~ection of o.37 x 1o-8 gAt Tl/kg minish the absorption of iron (10 ng-at 59Fe-(FeCl3). as 2o4Tl-(Tl2so4) the 2o Tl-activity in plasma fell within After administration of 10 ng-at 59Fe-(FeCl3) together 2o min to aböut 2o% of the initial value. The halftime of with 90 ng-at cobalt, a higher anount in the nrueosa, but this rapid phase of distribution was 8 - 9 min. A second a diminished transfer of iron into the body was observed. slow phase of distribution had a halftime of 7o -75 min. The study of the time-dependence of this interaction re Ligature of the kidneys was of no major influence on either vealed, that cobalt inhibits the release of iron frcrn nru halft ime cosal cells into the blood. This is the reason why under certain experimental conditions a storage stagnation of Secretion of thallous ions into the GI-tract was measured iron in the nrucosal cells is to be seen. for o~e hour during the slow phase of distribution of The subcellular distribution of 59pe-(Fecl3) and 60co 2o4Tl -ions in the organism after the intravenous injec (CoC12) in nrucosal cell homogenates of d rats after ultra tion (dose see above). At the end of the experiment in centrifugation (180 (XX) g, 16 h, 2 - 4 °c) on a PVP/CsCl the jejunum (5 cm length) o.35 %, in the colon (7 cm solution shows a similar pattern for both metals. In 162gth) o.o8 % and in the starnach o.o2 % of the injected presence of 90 ng-at cobalt the subcellular distribution 2o Tl-dose was secreted. The results are discussed with of 10 ng-at 59Fe-(FeC13) is not changed. This enphasizes respect of a pcssible secretion mechanism for pctassium the finding, that cobalt does not influence the uptake of ions in the GI-tract which due to the common physicocherni iron into the nrucosa. cal properties of either ion species might be used also by thallous ions. Institut für Pharmakologie und Toxikologie der RU:B, Im I.Dttental, D - 4630 Bochum Institut für Pharmakologie· und Toxikologie der Ruhr-Uni Institut für Pharmakologie und Toxikologie der Universität versität, D-463o Bochum, Postfach 1o2148, Im Lettental des Saarlandes, D - 6650 Homburg/Saar 2 4 DETERMINATION OF THE AMOUNT OF MUCOSAL TRANSFER CORRELATION BETWEEN THE 51crEDTA CLEARANCE AND THE RIN IN THE UPPER SMALL INTESTINE (DUODENUM, JEJU SECRETION OF FLUID AND ELECTROLYTES UNDER THE INFLUENCE NUM) OF IRON DEFICIENT RATS OF DEOXYCHOLATE (DC) IN THE RAT COLON. K. Osterloh and K. Ehrlich K. J. GOERG, G. NELL, and W. SPECHT Huebers et al. detected a non-ferritin protein What is the primary determinant for the changes in fluid binding iron in the mucosal cell of rats (Life and electrolyte movement in bile salt caused diarrhea? Sei. 10, 1141-1148, 1971). The properties of this In tied off intestinal loops a change of motility cannot protein were comparable to those of plasma trans be responsible for an increase of the fluid volume. ferrin (ptf). Today this protein is called muco Increased mucosal cAMP content and increased adenylate sal transferrin (mtf). cyclase activity let to the conclusion that DC is effec Immunological investigations indicated a tive via an activation of the adenylate cyclase activity close relationship between mtf and ptf. Using analogously to the action of cholera toxin. In cantrast antiserum against purified ptf precipitations to cholera toxin, which decreases the paracellular per with mtf were achieved by application of diffe meability of the rat colanie mucosa, DC increases the rent techniques. One of these methods, the Manci mucosal permeability. ni test, was found to be suitable for estimating If this increase of epithelial permeability is responsible the amount of mtf in the mucosa of iron-deficient for the enhanced fluid production by DC, there should be rats. The duodenum and the upper jejunum (total: a dose dependant correlation between the increase of fluid 29 cm starting with the pylorus) were used. The production and the increase of permeability. The rat colon iron solution (59Fe-FeC13 ~ 200000 cpm in 2 ml was perfused in vivo. Net water, Na, Cl and K fluxes were 0.9% NaCl, pH 2) was filled into the tied-off measured and permeability was examined by determining the segment and remained there for 10 min. Mtf was appearance of ~lcrEDTA in the colanie lumen after i.v. isolated by homogenisation, centrifugation application. No change of the net water, Na and Cl fluxes (3000 g and 100000 g), column chromatography on and no alteration of the 51CrEDTA clearance were found Sepharose 6 B and ion-exchange chromatography on in presence of 1 mM DC. Only the K secretion was already DEAE-Sephadex A 50. maximally enhanced. Concentrations from 2 to 8 mM caused Using an albumin standard in all protein de a dose dependent increase of water, Na and Cl secretion terminations, 8- 11 1ug/cm mtf was found in the parallelly to an increase of the 51CrEDTA clearance. These examined small intestlne. This amount corresponds effects were reversibel. The correlation between the in well with the yield of purified mtf found by crease of fluid secretion and the increase of the epi Huebers (5.3 1ug/cm jejunum, doctors thesis Saar thelial permeability suggests that the effect on permea brücken 1972). Chromatographical purification did bility is the predominant factor in the pathogenesis of not cause appreciable losses of mtf, however, mtf the bile salt induced diarrhea. appeared to be lost during the concentration steps of the protein. Department of Pharmacology and Toxicology, University of the Saarland, D-665 Homburg/Saar. Institut für Pharmakologie und Toxikologie der Ruhr-Universität D4630 Bochum Postfach 102148; Im Lattental R2 7 PROBENECID EFFECTS ON DISTRIBUTION AND ELIMIN ATION OF BENZYLPENICILLIN IN THE RAT * H.Bergholz, R,R,Erttmann, and K,H,Damm Previous studies of the effects of probenecid on penicillin distribution indicate that inhibition of renal secretion is not the only effect by which elevated plasma levels can be explained (Ziv and Sulman, Arch.int,Pharmacodyn, 207, 373, 1974), We have investigated the effect of ~0 mg /kg b,W, probenecid on distribution and bile ex cretion of C14 benzylpenicillin (bp) 5-90 min after i,p,application of 25 mg/kg b,w. Radioac tivity was measured by scintillation counting and bp concentration was calculated by use of internal standards, It was found that under probenecid the concentration of bp in plasma, cerebraspinal fluid and skeletal muscle in creased up to 2- to .3fold over the controls, At the same time the values in liver and kidney were lowered from 30 to 70 percent of the con trols and consequently the tissue/plasma ratio of bp was decreased from 6.2 to 2,8 in the liver and from 6,3 to 2.3 in the kidney, The bile ex cretion of bp was not significantly influenced by probenecid, But the half time of bp calcu lated was increased from 24,9 min to 33,2 min by probenecid while the volume of distribution Substrate Conc. Penneation (%) and the total clearance were lowered consider ,uM IA.nnen ... Blood Blood - Lumen ably (from 312 to 128 ml and from 7,4 to 2,85 I Thio 100 8.0 ++ 0 .20 (10) 6.1 ++ 0 .44 ( 8) ml/min, respectively). The results indicate Dig 1 0.49 0.04 (13) 5.6 0.33 (14) that besides the inhibition of renal tubular + + H2-Dig 1 0.48 + 0.05 ( 8) 7.7 + 0.63 (10) secretion other effects do contribute to the Ouab 1 0.25 +0 .08 ( 8) 0.57 +0 .16 ( 8) elevated plasma levels of bp following probene Nß-Mr.Sk:cJol p lcxx1:0> 00..8543 +0 0..0360 (( 115)) 0o.. 6791 +0 0..1151 (( 95)) cid application, Pharmakologisches Institut der Universität Institut für Phannakologie uni Toxikologie der Ruhr-Uni ~-2000 Harnburg 20, Martinistraße 52 versität, Im !Dttental, D-4630 Bochum Universitätskinderklinik FU D-1000 Berlin 19 6 8 BINDING OF DRUGS TO MUSCLE TISSUE: DRUG INTER RESORPTION RATE OF Mg AND Al FROM ANTACIDA REMEDlES - ACTIONS B. Fichtl, H. Kurz, I. Wachter, A. Ziegler INFLUENCES ON THE DISTRIBUTION OF ELECTROLYTES AND TRACE ELEMENTS Skeletal muscle of rabbits was homogenized with equal H. P. Bertram volume of isotonic phosphate buffer pH 7. 0. The binding of drugs (lo-4 M/1) was determined by ultrafiltration. The concentration of the unbound drug (cu) increased Tnohen -paobslyovrbaalebnlet . cIanti oenhsre innie arnetnacaild fsa cilaunrneo tA ble- croengtaaridneindg a s significantly (p < 0. 01) in the presence of a secend drug drugs are used to control hyperphosphataemia. Resorbed Al in equimolar concentrations in the following cases: is discussed to play a role in dialysis encephalopathy Drug Influenced by % Change of cu ssyunfdfircoimeen.c yW e anexda mdainileyd pinattaikeen tos f (5n =g A68l()O Hw) ith. Trehne apll aisnm a Phenprocoumon Tolbutamide + 23 Al of the treated patients was significantly higher Phenprocoumon Phenylbutazone + 10 (3,o6 umol/1) than in the control group (o,87). In the Quinine Promethazine + 22 same specimens Zn shows a slight decrease, Cu an elevatioß Morphine Phenylbutazone +11 The amount of Al-absorption by means of flameless atomic Chlorpromazine Suramin _3 + 85 absorption spectrophotometry was also measured after a Quinine Desipramine (10 M/1) + 27 single therapeutical dose in normal individuals. Tc 15 Nitrosalicylic acid . Phenylbutazone ( 10-3M/l) + 14 healthy volunteers different antacids were given: Al(OH)3; mixture of Caco3+Al(OH)3+Mg (OH)2; complex basic Al-Mg carbonate. Evaluation of the kinetic values was made for On the other hand the concentration of the unbound each person separately under standard-conditions with amount of sulfadimethoxine decreased in the presence special regard to food. Nearly all probands showed a of phenylbutazone by 15%. distinct Al-Absorption. Since the urinary Al-levels are Insignificantly or not influenced was the binding of nitro not directly correlated with the plasma-Al, beside the salicylic acid (by atropine, chlorpromazine). sulfadi single Al-estimation in urine at different times a 24-h methoxine (by quinine, sulfinpyrazone), phenprocoumon urine collection was made to reveal the total renal Al (by chlorpromazine). nitrofurantoin (by phenylbutaz.one). output. Maximum of resorption was reached after 2 - 3 hrs. Mg-containing antacids caused a distinct increase in Mg thiopental (by phenylbutazone). mecamylamine (by thio plasma-levels, but still remaining in the normal range. pental, nitrofurantoin), tolbutamide (by phenylbutazone), Possible interactions with electrolytes and trace elements quinine (by chlordiazepoxide, phenylbutazone), morphine lead to the determination of Ca, Na, K, Fe, Cu, Zn, Cr in (by promethazine), chlorpromazine (by thiopental). the same specimens. In order to get more detailed informa tion on possible pathogenetic processes it seems to be Pharmakologisches Institut der Universität München, useful to lock for a "metal fingerprint" in biological Nussbaumstrasse 26, D-8000 München 2 samples. Institute of Pharmacology and Toxicology, University of Münster, Westring 12, D-44oo Münster R3 9 11 DISPOSITION AND ANTICOAGULANT ACTIVITY OF THE ENANTIOMERS EXCRETION OF AN ANALOGON OF CLONIDINE COMPA~ OF PHENPROCOUMON IN PHENOBARBITAL PRETREATED RATS RED WITH CLONIDINE IN RATS. U. Gundert-Remy W. Schmidt and E. Weber An analogon of clonidine substituted in the The purpose of this study was to assess in rats the benzerre ring with bromide instead of chlo effect of enzyme induction on the stereoselective dis ride was given to female rats in a dose which position and anticoagulant activity of phenprocoumon. has no effect on the blood pressure. The sub stance was randomly tritiated (specific acti The experiments were perforrned in untreated and pheno vity 3.76 mCi/mg; NEN). The radioactive puri barbital pretreated (75 mg/kg for 4 days) male inbred ty amounted to 96 -97 %. Wistar-Lewis rats following single i.v. injections (0.6 In animals with cannulated bile duct 22.5 ! mg/kg) of S(-) or R(+)phenprocoumon. 2.1% of the radioactivity were excreted with Phenobarbital pretreatment caused an increase in the eli the bile. Over 9o % of the total radioacti mination rate and a decrease in the total anticoagulant vity was found to run with an Rf-value of effect per dose of both enantiomers. The plasma concen o.o7 in the systeme used. The Rf-value of the tration-effect relationship of the enantiomers was not parent compound was 0.85 using thin layer chro significantly affected by pretreatment with phenobarbital. matography. After giving clonidine the bili The synthesis rate of prothrombin complex activity prior ary excr~tion of the radioactivity amounted to the injection of phenprocoumon was higher in phenobar to 15.2 - 2.1% of the dose. About 8o% were bital pretreated rats than in control rats, indicating not the parent comp~und. ~he bile cannulated that phenobarbital induces the synthesis of clotting rats excreted 37.6 - 1o.o% of the dose of factors. the clonidine analog~n with the urine. Only a small part of the radioactivity was due to The intrinsic elimination rate constant and to a less de the parent sub~tance. The figure for cloni gree also the fraction of dose in the liver of both enan dine was 48.1 - 9.9% of the given radioacti tiomers increased after pretreatment with phenobarbital. vity in the urine from which about 8o% was The former was the result of enzyme induction, the latter the parent CO!lJ_pound. + due to the increase in liver weight. There was no differ In rats with ligated bile duct 66.2 - 5.2% ence between S(-) and R(+)phenprocoumon in the relative were excreted urinary when the clonidine ana changes of the pharmacokinetic parameters after pretreat logonwas given.The main part of"the radio ment with phenobarbital. activity accounted for metabolites. T~e uri nary excretion of clonidine was 74.o - 7.1% under the same conditions. 7o% were unchanged. The clonidine analogen was handled in the same manner as clonidine with respect to the bili ary excretion. Comparing the urinary excretion a greater part of the radioactivity was found Pharmakologisches Institut der Universität Mainz, as unchanged substance after clonidine. Obere Zahlbacher Str. 67, D-6500 Mainz Abt.f. Klin.Pharm. Med. Univ.Klini~, 69 HD 10 12 IN VIVO STUDIES ON THE INTERACTION BETWEEN PHENPRO A UNIVERSAL AND SENSITIVE METROD FüR GAS CHROMATOGRAPHie COUMON AND ACETYLSALICYLIC ACID OR PHENYLBUTAZO- DETERMINATION OF VOLATILE SUBSTRATES AND METABOLITES NE H.-M. Brinkmann, H.H. Jess, K.-U. Seiler W. Dünges, and K. Kiesel After intravenous injection of a loading dose of 3H-phenprocoumon The concentration of solutes from aqueous solutions in (P) to rabbits, the drug was infused for a period of 10 hours. By this the "l range is still a problern in gas chromatographic procedure a steady state concentration for total P (CssT) of 19 trace analysis (e.g. J.S. Fritz, Ace. Chem. Res. 10, 67, ug/ml plasma and for free P (CssF) of 3.4% of CssT was attained 1977). -- immediately after injection. lnterstitial fluid (IF) was drawn from Standardized extraction and extract concentration proce tissue cages implanted subcutaneously according to D. CHISHOLM dures are described for the g c analysis of volatile sub et al. (Brit med. J. 1, 569-573, 1973). After 7 to 10 hrs the total stances in sub-ml amounts of aquueous solutions. Extrac tion by stirring (P.L. Kirk, Adv. Chrom. 5, 79, 1968) was concentrations of P in this fluid amounted to 55% of the correspon combined with concentration under partial-reflux (K. ding plasma value, the CssF being 4.3% of the CssT in the IF. 5 Beyermannet al., Z. Anal. Chem. 251, 289, 1970). Techni hours after starting the application of P acetylsalicylic acid (AS) cal improvements have resulted in~ean blanks and high or phenylbutazone (PB) were also odministered by combination of reproducibility (W. Dünges and K. Kiesel in "Assay of a loading dose ond subsequent infusion. The CSST of AS and of biological samples for drugs and other trace compounds" PB were in the range of 100 ug/ml and 70 ug/mf plasma, respective E. Reid, ed., in press). ly. lmmediately upon oddition of AS or PB the free fraction of P in 0-nitrotoluene, o-nitro-anisole, phenol and benzylalcohol the plasma increased to 4.3% and 5.5% resp., andin the IF to in ppM amounts were extracted from 250 "1 water with ethyl acetate. The volume of the extracts was reduced to 6,4% (AS) and 6.1% (PB), and were permanentely maintained. ln 5 "l.Glass capillary g c according to K. Grob was then spite of the fact that both AS and PB reduce the protein binding of performed. The g c peak ratios: compounds/internal stan P in plasma and IF, opposite effects were observed with resprect to dards were similar to those from test runs. The recovery CssT and CssF. Upon addition of AS the CssT and CssF in both rates were 60 to 80%. Six complete pre-chromatographic compartments were reduced to lower Ieveis (75%). This moy be experiments were performed in 80 min. explained by diffusion of disploced P into the intracellular space, Presented are: the possibilities of the method and de whare the protein binding appears nottobe influenced by AS. After tailed working instructions. The g c determination of the above and related compounds addition of PB, however, the CSST was found to be unaltered in in nanogram amounts seems of general methodological in plasma and IF, while the CssF were considerably increased. lt terest, e.g. in pharmacological studies of microsomal may be assumed that the PB will intracellularly compete with hydroxylation. protein bound P thus increasing the concentration of free P also within the cells. Therefore a concentration gradient for free P does not exist between extra-and intracellular space. Hence, after administration of PB the free P concentrations are elevated in oll compartments accessible for P and PB. Pharmakologisches Institut der Universität Mainz, Department of Pharmacology, University of Kiel, D 23 Kiel, Obere Zahlbacher Str. 67, D-6500 Mainz Hospitalstrasse 4 - 6