Deutsche Pharmakologische Gesellschaft: Abstracts of the 19. Spring Meeting March 14–17, 1978, Mainz

74 Pages·1978·6.471 MB·English

by  G. Becker (auth.)

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