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0031-6997/84/36O4-0337$02.OO/OPHARMACOLOGICAL REVIEWS
Copyright © 1984 by The American Society for Pharmacology and Experimental Therapeutics
Index
Pharmacological Reviews
Volume 36
1984
Vol. 36, No.4
Printedin U.S.A.
Acetylenes, mechanism-based inactivators of isomerases, oxidases, andpyridoxal-phosphate-linked and flavin-linked enzymes, 120
6-Acetylmethylenepenicillanic acid, �-lactamase inhibition (fig.), 137
a-Adrenoceptor agonists, structure-activity relationships for efficacy
and affinity of (fig.), 209
a-Adrenoceptors, sympathetic efferents and agonists at, modulation of
lung surfactant secretion rate, 79
�9-Adrenoceptors
agonists and antagonists at, modulation of lung surfactant secretion
rate, 77
enhancement of surfactant secretion by agonists at (table), 77
Aflatoxin B1
cholestasis induced by, 15
Age, effects on biliary excretion of xenobiotics, 35
Aging, nutritional factors, modulating effects on, 123S
Agonism, selective, 189
Agonist affinity, relative efficacy and, measurement of, 192
Agonists
different ratios of efficacy and affinity, effects of changing receptornumber on (fig.), 191
dose-response curves, 183
EC5O and equilibrium dissociation constants, relationship between
(table), 186
full and partial, effects of receptor coupling on responses to (fig.),
192
potency ratios, 188
quantification of responses to, 183
tissue sensitivity to, methods to increase (table), 201
Amidines, inhibitor of alternative pathway, 238
Amino acids
derivatives and, inhibitor of alternative pathway, 238
derivatives and, inhibitor of classical pathway, 234
multienzyme system to convert urea and ammonia to (fig. ), 314
Anders, M. W., and Robert G. Carlson (guest editors), Toxicology:
Determinants of susceptibility and predictability, 1S-182S
Anders, M. W., Joe D. Burek, RObert G. Carlson, John L. Emerson,
George C. Fuller, J. E. LeBeau, Leland Loose, Laurnie W.Nelson, Robert A. Nelson, Emil A. Pfitzer and David H.
Swenson. Summary of the workshop of toxicology, 35
Androgens, physiological and synthetic, mediation of inappropriate
biological effecte, 355
Anhydride procedure, mixed, binding of drug molecules to macromo-
lecular carriers, 293
Animal models, whole, in safety evaluation, 177S
Anthralinates, inhibitor of classical pathway, 230
Antibody-drug conjugates, drug/enzyme carriers, 306
Antibiotics
effect on cholestasis, 16
effect on enterohepatic circulation, 44
Antiestrogen(s)
design (fig.), 266
estrogens with rapid dissociation rate from the estrogen receptor
248
general classification of, 248
general pharmacology, 248
metabolism, 250
in vitro, 252
337
laboratory animals in vivo, 252
nonsteroidal (fig.), 247, 265
nonsteroidal with a high binding affinity for the estrogen receptor(fig.), 248
pharmacokinetics, 250
potential mechanisms of action of (fig.), 262
radiolabeled, 257
binding characteristics, to estrogen receptor, 257
commercially available (fig.), 258
synthesis of, for study of metabolism in animals, 250
species differences, 249
structure-activity relationships, 262
in vitro studies, 265
in vivo studies, 263
tamoxifen and its metabolites, analytical techniques for detection of,
250
triphenylethylene derivatives, 248
Antiestrogen action
biochemical pharmacology of, 245
in vitro studies, 256
in vivo studies, 255
Antiestrogen binding sites, biological function, 260
Antiestrogenic activity, substituted 3,4 dihydronaphthalenes in imma-
ture rats (fig.), 263
Antiestrogenic mechanisms, 261
Arsenic, biliary excretion of, 32
Artery, femoral, effect of angle of cut, on responses to norepinephrine,
(fig.), 171
Arthus reaction
complement deposition at site of (fig.), 232
computerized area integrator for quantification ofcellular infiltration
of(fig.), 227
damaged venule at site of leukocyte accumulation (fig.), 228
Asghar, Syed Shafi. Pharmacological manipulation of complement
system, 223
Atherosclerotic process, heparin and, 91
ATPase(Na� + Ki-activated cardiac glycosides interaction with, 143
Na,K-, conformation necessary for ouabain binding, 145
Na,K-, digitalis glycosides and, 144Na,K-, effect of nystetin on (�V)vanadate binding to microsomal
Na,K-ATPase from pig kidney, 156
Na,K-, models for ouabain interaction with, 148
Na,K-, modulation of, and the consequences for ouabain binding,
157
Na,K-, ouabain as a tool in studies of, 144Na,K-, ouabain-bound, reactive states of, 152
Na,K-, use of ouabain binding capacity for characterization of, 156
Autonomic nervous system, lung surfactant secretion rate, modulation
of, 77
Barbiturates, affect on bile flow, 12
Bardin, C. Wayne. See J#{228}nneand Bardin, 35S
Barrett, J. Carl, Thomas W. Hesterberg and David G. Thomassen. Use
of cell transformation systems for carcinogenicity testing and
mechanistic studies of carcinogenesis, 535
Basal lemma, barrier to drug delivery, 283
338 INDEX
Benzamidines, inhibitor of classical pathway, 229
Bileacid-dependent flow, 6, 7
canicular, ductular modification, 9chemicals excreted into, classification of, 26comparison of, in different species (table), 6
historical aspects, 2
physicochemical characteristics of chemicals excreted into, 33
Bile acids
biliary excretion, 30
biliary excretion of xenobiotics, effect on, 39
effect on hepatic uptake, 20enterohepatic circulation, 42hepatic uptake, 23
relationship with cholesterol and phospholipids (fig.), 17
Bile composition, 5
Bile flow
barbiturate effect on, 12somatostatin effect on, 16
Bile flow versus bile acid secretion, linear extrapolation of (fig.), 7
Bile formation, 5
alteration of, 11ethanol effect on, 16
hepatic uptake, and biliary excretion, mechanisms of, 1
neurohumoral control of, 10osmotic ultrafiltration, 6
Biliary excretion
bile acids, 30
bilirubin, 29
chemicals conjugated with glucuronic acid, 29
chemicals excreted into bile, classification, 26
chemicals not biotransformed, 29
cholephils, 27
compounds conjugated with glutathione, 28
indocyanine green, not biotransformed, 29
mechanisms of, 1
metal, glutathione, role, 33
metals,31
morphological perspectives, 3
organic anions, 28
organic cations, 30
organic chemicals, neutral, 31
rose bengal, not biotransformed, 29xenobiotics
biological factors influencing, 33
pharmacological factors influencing, 37
Bilirubin
biliary excretion of, 29
hepatic uptake, effect on, 21
Blood, effects of heparin in, 96
Blood supply to liver, by hepatic artery and portal vein (fig.), 3, 4
Bresnick, Edward, Robert Foldes and Ronald N. Hines. Induction of
cytochrome P450 by xenobiotics, 43S
Burek, Joe D., See Anders et al., 3S
C8-tetraxnethylammonium, antagonism of responses of guinea pig ileal
longitudinal smooth muscle to (fig.), 204
Cadmium
biliary excretion of, 32
hepatic uptake, biphasic mechanism, 23
Carbenapenams, �3-lactamase inhibition (fig.), 137
Carbodiimides, binding of drug molecules to macromolecules carriers,
292
Carcinogenesis, celltransformation systems fortesting and mechanistic
studies of, 53S
Carcinogenicity testing, use of cell transformation systems for, 53S
Cardiac glycosides
interaction of, with (Na� + K�)-activated ATPase, 143
sodium pump and, 143
Carlson, Robert G. See Anders and Carison, 15-1825
Carison, Robert G. See Anders et al., 35
Cell injury
irreversible, 77S
mechanism of, with hepatotoxic chemicals, 715
Cellsartificial, drug/enzyme carriers, 313
barrier to drug delivery, 284
encapsulated, drug/enzyme carriers, 313
Cell transformation systems, use of, for testing and mechanistic studies
of carcinogenesis, 535
Chang, Chia-Cheng. See Trosko and Chang, 1375
Chiorophenothiazine suiphonate, inhibition of interaction of B-deter-
minant of C3 with anti-B-determinant by (fig.), 233
Chlorotoxicants, biliary excretion of xenobiotics, effect on, 38
Cholelithiasis, See also Gallstone disease
cholesterol insolubility, association with, 16
Cholephils, biliary excretion of, 27
Choleresis, effect on bile flow, 11
Cholestasis
drug-induced “intrahepatic cholestasis,” 12
extrahepatic, 12
manganese-bilirubin induced, 13
Cholesterol
insolubility of, associated with choleithiasis, 16
relationship with bile acids and phospholipids (fig.), 17
Chytil, Frank. Retinoic acid. Biochemistry, pharmacology, toxicology,
and therapeutic use, 935
Circulation, enterohepatic, 41
Cis-aconitic anhydride, binding of drug molecules to macromolecular
carriers, 293Clavulanic acid, fi-lactamase inactivation (fig.), 137
Complementactivation, inhibition of excessive, by heparin, 97
consuming abilities of polyanions (table), 225deposition at the Arthus reaction site by (fig.), 232
potentiators of natural Cl inhibitor, 237synthetic polypeptides that inhibit or consume (table), 224
Complement system, pharmacological manipulation of, 223
Copper, biliary excretion of, 31
Cyanuric chloride, binding of drug molecules to macromolecular car-
riers, 294
Cyclic nucleotides, lung surfactant secretion rate, role in, 81
Cyclopropanes, mechanism-based inactivators of oxidases, 128
Cytochrome P450, induction of, by xenobiotics, 435
Dent, John G., See Anders et al., 3S
Diamines, inhibitor of claseical pathway, 234
Diaxo, -containing mechanism-based enzyme inactivators, 130
Diazo linkages, binding of drug molecules to macromolecular carriers,
293
Digitalis, -induced inotropy, 143
Digitalis glycosides, Na,K-ATPase and, 144
3,4-Dihydronaphthalenes, substituted, relative antiestrogenic activity
of, in immature rate (fig.), 263
Diphenyldiamidines
inhibition of esterolytic activities of Cli and CI#{235}by (table), 231
inhibition of interaction of B-determinant of C3 with anti-B-deter-
minant by (fig.), 231
DNA, toxicity-induced aberrant methylation of, and its repair, 195
Dose-response curves, drug receptor interaction, 183
Doull, John. The past, present, and future of toxicology, 155
Drug-carrier conjugation, methods of, 289
Drug carriers, microspheres as, 315
Drug delivery
basal lamina barrier, 283
brain specific, prodrug approach (fig.), 321
INDEX 339
cellular barriers, 284
controlled
biological approaches, 277
oligonucleotides as drugs, 323
overview of (table), 288
pharmacologically active antireceptor antibodies, 322
prodrug delivery systems, 320
targeting to cellular carbohydrate binding proteins, 320
technologies for, 287
endothelial barrier, 280
reticuloendotheial barrier, 283
selective, barriers to, 279
targeting problem, 286
Drug delivery systems
liposomal, 296
sustained, 295
Drug/enzyme carriers
antibodies as, 305artificial cells, 313
cellular, 311
encapsulated cells, 313
macromolecules as, 317
semipermeable aqueous microcapsules, 313Drug nutrient interaction, therapeutic significance, in the elderly, 109S
Drug receptor(s)
methods of classification, 188
pharmacological characterization of, in isolated tissues (table), 174
Drug receptor theory, 184
Drugschemical degradation of, 174
drug receptors and, classification of, in isolated tissues, 165
incorporation of, in liposomes, 297
liposomal anti-infectious, 302
liposomal antineoplastic, 300
liposomal antitumor, effects of (table), 301new, relevance of isolated tissue studies to, 208
oligonucleotides as, 323
release of endogenous substances, 174
removal of, by tissues, 176
stimulation of synthesis and/or lung maturation (table), 85
Embryo, whole, use ofculture for evaluating toxicity and teratogenicity,
1455
Emmerson, John L. See Anders et al.; 3S
Endogenous substances, release by agoniste, in tissues (table), 175
Endothelial cells, transcytosis in (fig.), 282
Endotheliumbarrier to drug delivery, 280
heparin effects on, 93
injury prevention of, by heparin, 93
lipoprotein uptake by, inhibition of, by heparin, 96
restoration of normal electronegativity, by heparin, 93
Endotoxins, hepatic uptake, 24
Engelberg, Hyman. Heparin and the atherosclerotic process, 91Enslein, Kurt. Estimation of toxicological endpoints by structure-
activity relationships, 131S
Enterohepatic circulation, 41; (fig.), 42
bile acids, 42
endogenous compounds, 43xenobiotics, 43
Enterohepatic cycling
antibiotics, 44binding agents, 43
factors influencing, 43Enzyme(s)
diazo-cont.aining mechanism-based inactivators, 130
flavin-linked
acetylenes, mechanism-based inactivators of, 120
olefins, mechanism-based inactivatora of, 114
microsomal, effects on bile flow, 12
native or detergent-treated, characterization, 156
ouabain complexes, information obtained with vanadate, 154
P-450mechanism-based inactivators of (table), 121olefins, mechanism-based inactivators of, 114
pyridoxal-phosphate-linked
acetylenes, mechanism-based inactivators of, 120
fluorocarbons, mechanism-based inactivators of, 126
olefins, mechanism-based inactivators of, 114
Enzyme carriers, drug. See Drug/enzyme carriersEnzyme inactivators
kinetics of inhibition, 112
mechanism-based, 111
acetylenes, 120
asdrugs, 135,138
catalytic turnover, 113
chemical considerations, 114
design of, 113
inactivator design, formation of dead-end complexes in, 130
in vivo studies, 135
olefins, 114
stoichiometry of inactivation, 113
Enzyme inducers, microsomal, effect on biliary excretion of xenobiotics,37
Enzyme system, multi-, to convert urea and ammonia to simple amino
acids (fig.), 314
Erythromycins, cholestasis induced by, 14Esterases, mechanism-based inactivators of, 132
Estradiol
effect of a polyclonal antibody to the estrogen receptor on the binding
of (fig.), 259
hypothetic models to describe the binding of, with the ligand binding
site on the estrogen (fig.), 267
Estrogen(s)
drug receptor theories, 268
nonsteroidal (fig.), 265
nonsteroidal, structure-activity relationships, 246rapid dissociation rate from the estrogen receptor, 248
steroidal and nonsteroidal (fig.), 246
Estrogen action, anti-. See Antiestrogen action
Estrogen action
functional model (fig.), 255
models of, 253; (fig.), 254
Estrogen receptor
binding characteristics of radiolabeled antiestrogens to, 257
effect of a polyclonal antibody to, on the binding of estradiol and 4-hydroxytamoxifen to the ligand-binding site on (fig.), 259
estrogens with rapid dissociation rate from, 248
hypothetical models for estrogenic and antiestrogenic ligands binding
to (fig.), 268
interaction of agonists, antagonists, and partial agonists with (fig.),
269
nonsteroidal antiestrogens with a high binding affinity for (fig.), 248
Ethacrynic acid, biliary excretion of, after conjugation with glutathione,
28
Ethanol, bile formation, effect on, 16
Farber, John L., and Ronald J. Gerson. Mechanisms of cell injury with
hepatotoxic chemicals, 715
Fariss, Marc W. See Reed and Fariss, 25S
Fasting, effects on biliary excretion of xenobiotics, 36
Fernandes, Gabriel. Nutritional factors: Modulating effects on immune
function and aging, 123S
Fetus, lung surfactant system maturation in, 82
Fibrinolysis, enhancement by heparin, 97
Fibroblasts, drug/enzyme carriers, 312
340 INDEX
Flavin-linked enzymes
acetylenes, mechanism-based inactivators of, 120
olefmns, mechanism-based inactivators of, 114
Fluorocarbons, mechanism-based inactivators of pyridoxal-phosphate-
linked enzymes and oxidases, 126
Foldes, Robert. See Bresnick, et al., 435
Fuller, George C. See Anders et al., 3S
Gallstone disease. See also Cholelithiasis
Gallstones, medical treatment, 17
Gerson, Ronald J. See Farber and Gerson, 71S
Gilfillan, Alasdair M. See Hollingsworth and Gilfillan, 69
Glomerular injury, progressive, roles of dietary protein and compensa-
tory hypertrophy, lOiS
Glucose, production by $-adrenoceptor or glucagon stimulation, reac-
tions involved in production of (fig.), 187
Glucuronic acid, chemicals conjugated with, before biliary excretion,
29
Glutaraldehyde, binding of drug molecules to macromolecular carriers,
291
Glutathione
compounds conjugated with, before excretion into bile, 28
depletion and susceptibility, 255
role, in metal excretion, 33
Glycoproteins, desialylated, hepatic uptake, 24
Glycosides, cardiac. See Cardiac glycosides
Glycosides, digitalis. See Digitalis glycosides
Goldberg, Alan M. Approaches to the development of in vitro toxico-
logical methods, 1735
Grisham, Joe W., and Gary J. Smith. Predictive and mechanistic
evaluation of toxic responses in mammalian cell culture sys-tems, i5lS
Guanidines
inhibitor of alternative pathway, 238
inhibitor of classical pathway, 229
Hansen, Otto. Interaction of cardiac glycosides with (Na� + Ki-
activated ATPase. A biochemical link to digitalis-induced
inotropy, 143Heparin
atherosclerotic process and, 91
deficiency of plasma endogenous heparin activity, correction by, 101
displacement of lipoprotein lipase activity, 98
effectsof, in blood, 96
on high-density lipoproteins, 98
on reticuloendothelial system, 98
endothelial effects of, 93
fibrinolysis enhancement by, 97
hypercoagulability correction by, 96
inhibition of excessive complement activation by, 97
inhibition of lipoprotein uptake by endothelium, 96
inhibition of smooth muscle cell proliferation, 95
mitigation of harmful effects of thrombin, 94
platelet effects, 95
prostscyclin and, 95
serum triglycerides lowered by, 99
Hepatic. See also Liver
Hepatic clearance, xenobiotic elimination, efficiency of, 18
Hepatic uptake
bile acids, 23
bile acids, effect, 20
bilirubin, effect on, 21
desialylated glycoproteins, 24
endotoxins, 24
exogenous organic anions, effect on, 21
exogenous organic cations, effect on, 22
immune complexes, 24
immunoglobulins, 24
insulin, 24
in vivo multiple indicator dilution technique (fig.), 20
ligandin, 24
lipoproteins, 24
macromolecules in, 23
mechanisms of, 1
membrane receptors, 23
metallothionein, 25
metals, effect on, 23
methods of examination of, 19
neutral organic compounds, effect on, 22
proteins, intracellular, 24
Hepatobiliary transport, influencing factors, 33
Hepatotoxicants, biliary excretion of xenobiotics, effect on, 39
Hepatotoxic chemicals, mechanisms of cell injury with, 715
Hesterberg, Thomas W. See Barrett et al., 535
Hines, Ronald N. See Bresnick et al., 435
Hollingsworth, Michael, and Alasdair M. Gilfillan. The pharmacology
of lung surfactant secretion, 69
Hormone(s)
influence on bile flow, 10
stimulation of synthesis and/or lung maturation (table), 85
Hormone action, steroid receptors and, 35S
Hostetter, Thomas H. Progressive glomerular injury: Roles of dietary
protein and compensatory hypertrophy, 1015
Hypercoagulability, correction by heparin, 96
Hypertrophy, compensatory, role in progressive glomerular injury, 1015
Hypoglycemic drugs, hepatic reactions, 16
Hypothermia, experimental, effect on bile flow and biliary excretion,
15
Imidoesters, binding of drug molecules to macromolecular carriers, 294
Immune complexes, hepatic uptake, 24
Immune function, modulating effects of nutritional factors on, 123S
Immune system, molecular mimicry by (fig.), 323
Immunoglobulins, hepatic uptake, 24
Immunotoxins, drug/enzyme carriers, 308
Indenes, substituted, relative antifertility activity of, in the rat (fig.),
263
Indocyanine green, not biotransformed before biliary excretion, 29
Inhibitor(s)
of alternative pathway
amidines, 238
amino acids and their derivatives, 238
guanidines, 238
polyions, 238
polypeptides, 238
of classical pathway, 223
amino acids and their derivatives, 234
anthralinates, 230
benzamidines, 229
diaznines, 234
guanidines, 229
inorganics, 237
levopimaric derivatives, 232
phenylindandiones, 233
polyanions, 224
polynucleotides, 227
polypeptides, 224
potentiators of natural Cl inhibitor, 237
pyridinium sulphonylfluorides, 229
Inotropy, digitalis-induced, 143
Insulin, hepatic uptake, 24
Intercellular communication, chemical inhibition of, adaptive and non-
adaptive consequences of, 137S
Iron, hepatic uptake, 23
Isolated tissues. See under Tissues
INDEX 341
Isomerases, acetylenes, mechanism-based inactivators of, 120
isoproterenol, chronic, effect of, on rat atrial responses to 1-isoproter-
enol and prenalterol (fig.), 198
Isoproterenol, polymeric isoproterenol and, distribution of, in cat pap-
illary muscle (fig.), 177
James, Jacqueline L. See Smuckler and James, 77SJ#{224}nne, Olli A, and C. Wayne Bardin. Steroid receptors and hormone
action: Physiological and synthetic androgens and progestins
can mediate inappropriate biological effects, 355
Jordan, V. Craig. Biochemical pharmacology of antiestrogen action,
245
Kenakin, Terry F. The classification of drugs and drug receptors in
isolated tissues, 165
Kidney, progressive glomerular injury, roles of dietary protein and
compensatory hypertrophy, 1015
Klaassen, Curtis D., and John B. Watkins HI. Mechanisms of bile
formation, hepatic uptake, and biliary excretion, 1
�9-Lactamase
inactivation, by clavulanic acid and penicillanic acid sulfone (fig.),
137
inhibition by
6-acetylmethylenepenicillanic acid, mechanism (fig.), 137
6-13-bromopenicillanic acid (fig.), 138
carbenapenams, scheme, (fig.), 137
mechanism-based inactivators of, 132; (table), 135, 136
Lead, biliary excretion of, 31
LeBeau, J. E. See Anders et al., 35Leukocytes, drug/enzyme carriers, 312
Levopimaric acid derivatives, inhibitor of classical pathway, 232
Ligandin, hepatic uptake, 24
Lipid profile of lung fractions (table), 71
Lipoprotein lipase activity, displacement by heparin, 98
Lipoproteins
hepatic uptake, 24
high-density, heparin effect on, 98
uptake by endothelium, inhibition of, by heparin, 96
Liposomes
anti-infectious drugs, 302
antineoplastic drugs, 300
antitumor drugs, effects of (table), 301
behavior of, in vivo, 298
cell interactions, 298
drugs incorporated in, 297
immunomodulation with liposomal drugs, 304
overcoming drug resistance, 302
sustained release of, 302
targeting of, 299
toxicity reduction in the host, 302
types of (fig.), 297
uptake of, by tumors, 300
Lithocholate, toxic effects, 12
Liver. See also Hepatic
blood supply, by hepatic artery and portal vein (fig.), 3
blood supply to (fig.), 3, 4
first-pass effect, chemicals undergoing, 17
hypoglycemic drugs, reaction, 16
mechanisms of cell injury with hepatotoxic chemicals, 715
osmotic ultrafiltration, 6
xenobiotics, elimination by, 17
Liver injury, effect on biliary excretion of xenobiotics, 40
Liver structure, concepts of, 3
Loose, Leland. See Anders et al., 3S
Lung fractions, lipid profiles of (table), 71
Lung inflation, lung surfactant secretion regulated by, 82
Lung surfactant
biosynthetic pathways, 70
chemical nature of, 70
Lung surfactant secretion
enhancement, by agonists at �-adrenoceptors (table), 78
lung inflation, regulated by, 82
methods for study of, 74
isolated perfused lung, 75
lung lavage technique, 74
lung slice technique, 75
lung stability, 75
static lung compliance, 75
ultrastructural studies, 75
monitoring
biochemical measurement, 76
surface tension measurement, 76
perinatal period, 83
pharmacology of, 69
rate, modulation of, 77
agonists at /3-adrenoceptors, 77
antagonists at (3-adrenoceptors, 77
autonomic nervous system, 77
cyclic nucleotides, role in, 81
parasympathetic efferents and agonists at muscarinic receptors,
79
prostanoids, 80
sympathetic efferents and agonists at a-adrenoceptors, 79
sympathetic efferents at a-adrenoceptors, 79
Lung surfactant synthesis
pharmacological and hormonal agents that stimulate synthesis and!
or lung maturation (table), 85
rate, modulation of, 84
Lung surfactant system
autoradiographic studies, 72
biochemical studies, 71
exocytotic secretory process, example of, 70
maturation in fetus, 82
postsecretory events, 74
radiolabeling studies, 72
ultrastructural studies, 71
LY 1 17018, effect of injection of, on radioactivity levels in immature
rat uterus, vagina, and pituitary glands (fig.), 256
LY 126412, antiestrogen effect, in immature rate uterus (fig.), 248
Mammalian cell culture systems, toxic responses, predictive and mech-
anistic evaluation of, 1515
Manganese
biliary excretion of, 32
bilirubin-induced cholestasis, 13
Mercury, biliary excretion of, 32
Metabolism, antiestrogens, 250
Metallothionein, hepatic uptake, 25
Metals
biliary excretion, 31
effect on hepatic uptake, 23
Methylfurmethide, antagonism of responses of guinea pig ileal longi-
tudinal smooth muscle to (fig.), 204
Muscarinic receptors, parasympathetic efferents and agonists at, mod-
ulation of lung surfactant secretion rate, 79
a-Naphthylisothiocyanate, cholestaais induced by, 15
Nelson, Laurnie. See Anders et al., 3SNelson, Robert A. See Anders et al., 3S
Nerves, influence on bile flow, 10
Nervous system, autonomic. See Autonomic nervous system
Nitromifene, metabolism of, in vivo and in vitro (fig.), 253
Nutrient-drug interactions, significance of, in the elderly, 109S
Nutrition, modulating effects on immune function and aging, 123S
342 INDEX
Olefine, mechanism-based inactivators of pyridoxal-phosphate-linked,
flavin-linked, and P-450 enzymes, 114
Oligonucleotides, as drugs, 323
Organic anions, exogenous, effect on hepatic uptake, 21
Organic cationsbiliary excretion of, 30
exogenous, effect on hepatic uptake, 22
Organic compounds, neutral, effect on hepatic uptake, 22
Ouabain
binding
capacity, use of, for characterization ofNa,K-ATPase preparations
or the pump density of tissues, 156
ligand modulation of, 151
modulation of the Na,K-ATPase and the consequences for, 157
Na,K-ATPase conformation necessary for, 145potassium, role in, 147
requirements, 145
reversible, 147
bound, Na,K-ATPase, reactive states of, 152dissociation, effect of (Na� ATP) on, after (Mg� + P1)-facilitated or
(Mg� + V)-facilitated binding (fig.), 154
interaction with Na,K-ATPase, models for, 148
tool, in Na,K-ATPase studies, 144
Ouabain receptors, homogeneous and nonuniform populations of, 149
Oxidases
ecetylenes, mechanism-based inactivators of, 120
cyclopropanes, mechanism-based inactivators of, 128
pyridoxal-phosphate-linked, fluorocarbons, mechanism-based mac-
tivators of, 126
P.450 enzymes
mechanism-based inactivators of (table), 121
olefins, mechanism-based inactivetors of, 114Penicillanic acid sulfone, �-lactamase inactivation (fig.), 137
Perinetal period, lung surfectant secretion, 83
Periodate oxidation, binding of drug molecules to macromolecular
carriers, 291
Pfitzer, Emil A. See Anders et al., 35
Phalloidin, cholestasis induced by, 15
Phenanthrenes, fluorescent, conversion of triphenylethylenes to, byultraviolet activation (fig.), 251
Phenol-3,6-dibromphthalein dilsulfonate, not biotransformed before
biliary excretion, 30Phenothiazines, cholestaeis induced by, 13
Phenothiazine sulphonate, inhibition of interaction of B-determinant
of C3 with anti-B-determinant by (fig.), 233
Phenylindandiones, inhibitor of classical pathway, 233
Phosphatidylcholine, synthesis of, cytidine diphosphate choline path-
way responsible for (fig.), 72
Phospholipids
relationship with bile acids and cholesterol (fig.), 17
structures of (fig.), 71
Platelet, reaction to heparin, 95
Pneumocyte type 2
hamster lung (fig.), 73
rat lung (fig.), 73
Polyanionscomplement-consuming abilities of (table), 225
inhibitor of alternative pathway, 238
inhibitor of classical pathway, 224
Polynucleotides
inhibitor of classical pathway, 227
Polypeptides
inhibitor of alternative pathway, 238
inhibitor of classical pathway, 224synthetic, that inhibit or consume complement (table), 224
Potauium-ouabain antagonism, 147
Poznansky, Mark J., and Rudolph L. Juliano. Biological approaches to
the controlled deliverj’ of drugs: A critical review, 277
Pregnancy, effects on biliary excretion of xenobiotics, 36
Prodrug
brain specific drug delivery, approach (fig.), 321
delivery systems, 320
Progestins, physiological and synthetic, mediation of inappropriate
biological effects, 355
Propranolol, effects of, on responses of rat left atria to tyramine (fig.),
175
Prostacyclin, heparin and, 95
Prostanoids, lung surfactant secretion, involvement in, 80
Proteases, mechanism-based inactivators of, 132
Protein
dietary, role, in progressive glomerular injury, 1015
intracellular, hepatic uptake, 24Pyridinium sulphonylfluorides, inhibitor of classical pathway, 229
Pyridoxal-phosphate-linked enzymes
acetylenes, mechanism-based inactivators of, 120
fluorocarbons, mechanism-linked inactivators of, 126
olefins, mechanism-based inactivators of, 114
Pyridoxal-phosphate-linked oxidases, fluorocarbons, mechanism-based
inactivators of, 126
Rando, Robert R. Mechanism-based enzyme inactivators, ill
Receptor classification, operational concepts, 207
Receptor number
experimental manipulation of, 196
methods to decrease (table), 199
methods to increase (table), 200
Reed, Donald J., and Marc W. Fariss. Glutethione depletion and
suseeptibility, 255
Response, stimulus and, relationship between 185
Reticuloendothelial system, heparin effect on, 98
Reticuloendothelium, barrier to drug delivery, 283
Retinoic acid, biochemistry, pharmacology, toxicology, and therapeuticuse of, 93S
Roe, Daphne A. Therapeutic significance of drug-nutrient interactions
in the elderly, 109S
Rose bengal, not biotransformed before biliary excretion, 29
Sadler, T. W., and C. W. Warner. Use of whole embryo culture for
evaluating toxicity and teratogenicity, 1455
Safety evaluation, whole animals models in, 177
Schild regressions
in tissues with mixed receptor populations (fig.), 205
theoretical, for heterogeneous receptor populations (fig.), 206
variable fractional stimulus from a heterogeneous population, effects
on (fig.), 206
Secretory process, exocytotic, lung surfactant system as example of, 70
Sex, effects on biliary excretion of xenobiotics, 34
Shank, Ronald C. Toxicity-induced aberrant methylation of DNA and
its repair, 19S
Smith, Gary J. See Grisham and Smith, 1515
Smooth muscle cell proliferation, inhibition of, by heparin, 95
Smuckler, Edward A. and Jacqueline L. James. Irreversible cell injury,
775
Sodium pump, cardiac glycosides and, 143
Somatostatin, effect on bile flow, 16
Steroid receptors, hormone action and, 35S
Steroids, cholestasis induced by, 13
Stimulus
response and, relationship between, 185
tissue response as a function of, 185
Stimulus-response coupling, experimental manipulation of receptor
number and efficiency of, 196
Structure-activity relationships, toxicological endpoints, estimation by,
131S
N-Succinimydyl 3-(2-pyridyldithio)propionate (SPDP) binding of drug
molecules to macromolecular carriers, 294
INDEX 343
Zinc, hepatic uptake, biphasic mechanism, 23
Sulfobromophthalein (BSP), conjugated with glutathione before biliary
excretion, 28Swenson, David H. See Anders et al., 3S
Tamoxifen
antiestrogen effect, in immature rat uterus (fig.), 248
effect of different side chains on the antiestrogenic activity of (fig.),
264
4-hydroxy-
effect of a polyclonal antibody to the estrogen receptor on the
binding of (fig.), 259
hypothetic models to describe the binding of, with the ligand
binding site on the estrogen (fig.), 267
hydroxylated derivatives of, and antitumor activity of acetoxy deriv-
atives of triphenylbut-1-ene (fig.), 265
metabolism, by laboratory animals in vivo, 252
metabolites and
assay methods to measure concentration of, in biological fluids
(table), 251
comparison of concentration of, in patient blood duringTherapy
for breast cancer (table), 251
metabolites of (fig.), 250
analytical techniques for detection of, 250
pharmacokinetics of, 251
Teratogenicity, whole embryo culture, use of for evaluating, 1455
Thioester linkage, binding of drug molecules to macromolecular car-
riers, 295
Thomassen, David G. See Barrett et al., 53S
Thrombin, mitigation of harmful effects of, by heparin, 94
Tissue(s)
agonists that release endogenous substances in (table), 175
isolated
animal, 167
animal, commonly used (table), 168
binding studies and, 166
classification of drugs and drug receptors in, 165
comparisons, 173
equilibrium conditions in, 173
human (table), 170
preservation of tissue viability, 167
relevance to new drugs, 208
mixed receptor populations, Schild regressions in (fig.), 205
removal of drugs by, 176
responses to full and partial agonists, relationships between (fig.),
197
sensitization, relationship of, to uptake inhibition (fig.), 181variations, sources, 172
Tissue preparation, methods, 168
Tissue responses, measurement, 172
Tissue sensitivity
to agonists, methods to decrease (table), 200
to agonists, methods to increase (table), 201
Toxicity, whole embryo culture, use for evaluating, 145S
Toxicological endpoints, estimation of, by structure-activity relation-
ships, 131S
Toxicological methods, in vitro, development of, 173S
Toxicology
past, present, and future of, 155
workshop
determinants of susceptibility and predictability, 15-1825
summary, 35
Toxic responses, mammalian cell culture systems, predictive and mech-
anistic evaluation of, 1515
Triglycerides, serum, lowered by heparin, 99
Trioxifene, antiestrogen effect, in immature ret uterus (fig.), 248
Triphenylethylene(s)
conversion of, to fluorescent phenanthrenes by ultraviolet activation
(fig.), 251
geometric isomers of (fig.), 247
structure of fixed ring derivatives of, with different side chains (fig.),
264
Triphenylethylene derivatives, antiestrogene, 248
Trosko, James E., and Chia-Cheng Chang. Adaptive and nonadaptive
consequences of chemical inhibition of intercellular commu-
nication, 137S
Tumors, uptake of liposomes by, 300
Vanadate, information on enzyme-ouabain complexes obtained with,
154
Vascular pressure, influence on bile flow, 10
von Wittenau, M. Schach. Whole animal models in safety evaluation,
1775
Warner, C. W. See Sadler and Warner, 145S
Watkins, John B., III. See Klaassen and Watkins, 1
Xenobiotics
biliary excretion of
age, effects, 35
bile acids, effect, 39
biological factors influencing, 33
chlorotoxicants, effects on, 38
effect of liver injury, 40
enzyme inducers, effects, 37
fasting effects, 36
hepatotoxicants effects on, 39
pharmacological factors influencing, 37
pregnancy effects, 36
sex differences, 34species variation, 33
cytochrome P450 induction by, 435
enterohepatic circulation, 43
hepatic elimination of, 17
production of choleresis, 11