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