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PMID: 6194927 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S. Review

Assessment of methods to identify sources of interindividual pharmacokinetic variations.

Clinical pharmacokinetics ·Vol. 8 ·No. 5 ·1983-00-00 ·Pages 378-409

Vesell ES, Penno MB

Abstract

The advantages and limitations of the 2 most commonly used methods to investigate interindividual pharmacokinetic variations are reviewed. The first method is based on pharmacokinetic comparisons made after repeated administration of a model drug such as antipyrine, before, during and after imposition of a carefully controlled environmental perturbation. A principal virtue of the test is the use of each subject as a control. Subjects are usually under near basal conditions with respect to factors capable of altering hepatic drug-metabolising capacity. Exceedingly sensitive, the test yields highly reproducible results. It has been useful as a research tool in identifying environmental factors for which dose-response curves can be generated and compared. However, the test requires careful selection and control of subjects, and it may be hazardous to extrapolate results to subjects under different, non-basal, environmental conditions. This method most frequently involves antipyrine as the test compound, but other drugs can and have been used. The results disclose that many host factors that influence antipyrine disposition also affect the disposition of other drugs metabolised by hepatic mixed-function oxidases. Recent refinement of the antipyrine test involves measurement of the rate constant for formation of each of the 3 main metabolites of antipyrine. Sensitivity and specificity of the test are increased through examination of the effect of each factor on a separate hepatic cytochrome P-450. Due to the labouriousness of this procedure and its requirement for several days of urine collection from each subject, metabolite analysis will probably remain an experimental method not applicable for screening populations. The second method involves a particular model based on multiple regression analysis. Relying on correlations with historical data of a qualitative nature, previous applications of this method have been retrospective, rather than prospective. Several such correlations could not be confirmed in normal subjects under the conditions of a controlled prospective experiment. Thus, prospective studies need to be performed to check results obtained with this method. The model used appears to enjoy certain advantages, including speed, simplicity, and ease of execution.(ABSTRACT TRUNCATED AT 400 WORDS)

MeSH Terms
Acetylation Antipyrine/metabolism Dicumarol/metabolism Female Genetics Humans Individuality Kinetics Models, Biological Pedigree Pharmaceutical Preparations/metabolism Phenylbutazone/metabolism Pregnancy Regression Analysis Twins
Chemicals
Pharmaceutical Preparations Dicumarol Phenylbutazone Antipyrine
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Vesell E S
Penno M B
References (106)
106 references, click to expand
  1. Prediction of drug oxidation rates in man: lack of correlation with serum gamma-glutamyl transpeptidase and urinary excretion of D-glucaric acid and 6 beta-hydroxycortisol.
    Eur J Clin Pharmacol. 1974;7(1):71-5 PMID: 4153008
  2. Defective N-oxidation of sparteine in man: a new pharmacogenetic defect.
    Eur J Clin Pharmacol. 1979 Sep;16(3):183-7 PMID: 499318
  3. The antipyrine test in clinical pharmacology: conceptions and misconceptions.
    Clin Pharmacol Ther. 1979 Sep;26(3):275-86 PMID: 111889
  4. Studies on the disposition of antipyrine, aminopyrine, and phenacetin using plasma, saliva, and urine.
    Clin Pharmacol Ther. 1975 Sep;18(3):259-72 PMID: 1164816
  5. Anomalous results of studies on drug interaction in man. I. Nortriptyline and antipyrine.
    Pharmacology. 1975;13(2):101-11 PMID: 49899
  6. Genetic and environmental factors affecting ethanol metabolism in man.
    Clin Pharmacol Ther. 1971 Mar-Apr;12(2):192-201 PMID: 5102974
  7. Genetic control of drug levels in man: phenylbutazone.
    Science. 1968 Mar 29;159(3822):1479-80 PMID: 5753556
  8. Antipyrine kinetics in the elderly: prediction of age-related changes in benzodiazepine oxidizing capacity.
    J Pharmacol Exp Ther. 1982 Jan;220(1):120-6 PMID: 7053408
  9. Polymorphic oxidation of sparteine and debrisoquine: related pharmacogenetic entities.
    Clin Pharmacol Ther. 1982 Feb;31(2):184-6 PMID: 7056024
  10. Further observations on relationships between antipyrine half-life, clearance and volume of distribution: an appraisal of alternative kinetic parameters used to assess the elimination of antipyrine.
    Clin Pharmacokinet. 1980 May-Jun;5(3):263-73 PMID: 7389235
  11. Advances in pharmacogenetics.
    Prog Med Genet. 1973;9:291-367 PMID: 4123249
  12. Slow hydroxylation of nortriptyline and concomitant poor debrisoquine hydroxylation: clinical implications.
    Lancet. 1981 Mar 7;1(8219):560-1 PMID: 6111662
  13. The physiological disposition of dicumarol in man.
    J Pharmacol Exp Ther. 1950 Aug;99(4:1):409-20 PMID: 15437317
  14. Comparative metabolism of benzo[a]pyrene and drugs in human liver.
    Clin Pharmacol Ther. 1977 Feb;21(2):166-76 PMID: 837635
  15. Inheritance of phenytoin hypometabolism: a kinetic study of one family.
    Clin Pharmacol Ther. 1980 Jan;27(1):96-103 PMID: 7351122
  16. Polymorphism of carbon oxidation of drugs and clinical implications.
    Br Med J. 1978 Sep 2;2(6138):655-7 PMID: 151576
  17. Monogenic control of variations in antipyrine metabolite formation. New polymorphism of hepatic drug oxidation.
    J Clin Invest. 1983 Jun;71(6):1698-709 PMID: 6863539
  18. Genetic control of dicumarol levels in man.
    J Clin Invest. 1968 Dec;47(12):2657-63 PMID: 4177776
  19. Genetic control of interindividual variations in the inducibility of aryl hydrocarbon hydroxylase in cultured human lymphocytes.
    Cancer Res. 1976 Dec;36(12):4619-30 PMID: 63323
  20. Antipyrine: radioimmunoassay in plasma and saliva following administration of a high dose and a low dose.
    Clin Pharmacol Ther. 1976 Aug;20(2):219-26 PMID: 947654
  21. Pharmacogenetics: defective enzymes in relation to reactions to drugs.
    Annu Rev Med. 1972;23:453-68 PMID: 4118885
  22. High plasma concentrations of beta-receptor blocking drugs and deficient debrisoquine hydroxylation.
    Lancet. 1982 Feb 6;1(8267):333 PMID: 6120324
  23. Genetic variation in rates of antipyrine metabolite formation: a study in uninduced twins.
    Proc Natl Acad Sci U S A. 1981 Aug;78(8):5193-6 PMID: 6946467
  24. The use of antipyrine in the measurement of total body water in man.
    J Biol Chem. 1949 May;179(1):31-42 PMID: 18119217
  25. Ethnic differences in drug metabolism.
    Clin Pharmacokinet. 1982 Sep-Oct;7(5):373-400 PMID: 6754206
  26. E- and Z-10-hydroxylation of nortriptyline: relationship to polymorphic debrisoquine hydroxylation.
    Clin Pharmacol Ther. 1981 Aug;30(2):189-93 PMID: 7249504
  27. Enhanced phenacetin metabolism in human subjects fed charcoal-broiled beef.
    Clin Pharmacol Ther. 1976 Dec;20(6):633-42 PMID: 991534
  28. Adaptive increases in drug-metabolizing enzymes induced by phenobarbital and other drugs.
    J Pharmacol Exp Ther. 1960 Sep;130:1-8 PMID: 13811549
  29. Nortriptyline and antipyrine clearance in relation to debrisoquine hydroxylation in man.
    Life Sci. 1980 Nov 3;27(18):1673-7 PMID: 7442467
  30. Impaired oxidation of debrisoquine in patients with perhexiline neuropathy.
    Br Med J (Clin Res Ed). 1982 Jan 30;284(6312):295-9 PMID: 6277419
  31. Defective oxidation of drugs: pharmacokinetic and therapeutic implications.
    Clin Pharmacokinet. 1982 Jan-Feb;7(1):1-22 PMID: 7042170
  32. The fate of aminopyrine (pyramidon) in man and methods for the estimation of aminopyrine and its metabolites in biological material.
    J Pharmacol Exp Ther. 1950 Jun;99(2):171-84 PMID: 15437290
  33. Anomalous results of studies on drug interaction in man. III. Disulfiram and antipyrine.
    Pharmacology. 1975;13(6):481-91 PMID: 1221431
  34. Individual differences in the disposition of drugs metabolised in the body.
    Clin Pharmacokinet. 1978 Mar-Apr;3(2):155-75 PMID: 346288
  35. Genetic and environmental influence on halothane metabolism in twins.
    Clin Pharmacol Ther. 1971 Jan-Feb;12(1):50-5 PMID: 5099890
  36. Environmental effects on antipyrine half-life in man.
    Clin Pharmacol Ther. 1977 Nov;22(5 Pt 2):799-808 PMID: 913037
  37. Effect of cesarean section on neonatal body water spaces.
    N Engl J Med. 1971 Oct 14;285(16):887-91 PMID: 4939538
  38. PHARMACOGENETICS.
    Prog Med Genet. 1964;23:49-74 PMID: 14110077
  39. Stimulatory effect of brussels sprouts and cabbage on human drug metabolism.
    Clin Pharmacol Ther. 1979 Jan;25(1):88-95 PMID: 758247
  40. The fate of acetophenetidin in man and methods for the estimation of acetophenetidin and its metabolites in biological material.
    J Pharmacol Exp Ther. 1949 Sep;97(1):58-67 PMID: 18140117
  41. Gas chromatographic assessment of the reproducibility of phenazone plasma half-life in young healthy volunteers.
    Eur J Clin Pharmacol. 1974 Aug 23;7(5):381-5 PMID: 4418356
  42. Failure of cola nut chewing to alter antipyrine disposition in normal male subjects from a small town in South Central Pennsylvania.
    Clin Pharmacol Ther. 1979 Sep;26(3):287-93 PMID: 466922
  43. Environmental factors affecting antipyrine metabolism in London factory and office workers.
    Br J Clin Pharmacol. 1979 Mar;7(3):237-43 PMID: 427001
  44. Observations on the drug-induced synthesis of D-glucuronic, L-gulonic and L-ascorbic acids in rats.
    J Pharmacol Exp Ther. 1960 Jun;129:132-8 PMID: 13806253
  45. Intraindividual variation in drug disposition.
    Clin Pharmacol Ther. 1979 Oct;26(4):407-19 PMID: 314881
  46. The fate of pentobarbital in man and dog and a method for its estimation in biological material.
    J Pharmacol Exp Ther. 1953 Sep;109(1):26-34 PMID: 13097331
  47. MORPHOLOGICAL CHANGES IN THE LIVER ACCOMPANYING STIMULATION OF MICROSOMAL DRUG METABOLIZING ENZYME ACTIVITY BY PHENOBARBITAL, CHLORDANE, BENZPYRENE OR METHYL-CHOLANTHRENE IN RATS.
    J Pharmacol Exp Ther. 1965 Jan;147:112-9 PMID: 14255155
  48. Assay of antipyrine and its primary metabolites in plasma, saliva and urine by high-performance liquid chromatography and some preliminary results in man.
    Pharmacology. 1979;18(4):210-23 PMID: 461498
  49. Comparison of isoniazid concentrations in the blood of people of Japanese and European descent; therapeutic and genetic implications.
    Am Rev Tuberc. 1958 Dec;78(6):944-8 PMID: 13595241
  50. Studies on the different metabolic pathways of antipyrine in rats: influence of phenobarbital and 3-methylcholanthrene treatment.
    Xenobiotica. 1979 Nov;9(11):695-702 PMID: 119355
  51. Questionable relation of aryl hydrocarbon hydroxylase to lung-cancer risk.
    N Engl J Med. 1977 Aug 18;297(7):346-50 PMID: 876325
  52. Metabolism of drugs. LIX. A new metabolite of antipyrine.
    Biochem Pharmacol. 1968 Aug;17(8):1511-6 PMID: 5672814
  53. Forecasting individual pharmacokinetics.
    Clin Pharmacol Ther. 1979 Sep;26(3):294-305 PMID: 466923
  54. Salicylate metabolism in twins. Evidence suggesting a genetic influence and induction of salicylurate formation.
    J Clin Invest. 1977 Jul;60(1):32-42 PMID: 559691
  55. Impairment of drug metabolism in man by allopurinol and nortriptyline.
    N Engl J Med. 1970 Dec 31;283(27):1484-8 PMID: 4098480
  56. Family study of antipyrine clearance.
    Br Med J (Clin Res Ed). 1982 Jan 16;284(6310):150-2 PMID: 6799075
  57. Genetic control of nortriptyline kinetics in man: a study of relatives of propositi with high plasma concentrations.
    J Med Genet. 1971 Jun;8(2):129-35 PMID: 5096533
  58. Acetophenetidin sensitivity.
    Am J Dis Child. 1967 Jan;113(1):81-2 PMID: 6015912
  59. Debrisoquin hydroxylation polymorphism among Ghanaians and Caucasians.
    Clin Pharmacol Ther. 1979 Nov;26(5):584-91 PMID: 498701
  60. The fate of procaine in man following its intravenous administration and methods for the estimation of procaine and diethylaminoethanol.
    J Pharmacol Exp Ther. 1948 Dec;94(4):359-66 PMID: 18105653
  61. Liver failure and drug metabolism.
    Scand J Gastroenterol. 1975;10(3):293-7 PMID: 1138332
  62. The estimation of antipyrine in biological materials.
    J Biol Chem. 1949 May;179(1):25-9 PMID: 18119216
  63. On the significance of host factors that affect drug disposition.
    Clin Pharmacol Ther. 1982 Jan;31(1):1-7 PMID: 7053297
  64. Genetic control of phenylbutazone metabolism in man.
    Br Med J. 1970 Nov 7;4(5731):323-8 PMID: 5528753
  65. Drug metabolism in normal children, lead-poisoned children, and normal adults.
    Clin Pharmacol Ther. 1975 Feb;17(2):179-83 PMID: 804369
  66. Effect of environmental factors on drug metabolism: decreased plasma half-life of antipyrine in workers exposed to chlorinated hydrocarbon insecticides.
    Clin Pharmacol Ther. 1969 Sep-Oct;10(5):638-42 PMID: 5808460
  67. Genetic impairment of phenformin metabolism.
    Lancet. 1980 May 24;1(8178):1147 PMID: 6103491
  68. Factors affecting theophylline clearances: age, tobacco, marijuana, cirrhosis, congestive heart failure, obesity, oral contraceptives, benzodiazepines, barbiturates, and ethanol.
    J Pharm Sci. 1979 Nov;68(11):1358-66 PMID: 41932
  69. Genetic control of isoniazid metabolism in man.
    Br Med J. 1960 Aug 13;2(5197):485-91 PMID: 13820968
  70. Pharmacogenetics of tolbutamide metabolism in humans.
    Diabetes. 1979 Jan;28(1):41-51 PMID: 569611
  71. A case of deficiency of N-hydroxylation of amobarbital.
    Clin Pharmacol Ther. 1977 May;21(5):530-5 PMID: 558078
  72. Application of the phenotyped panel approach to the detection of polymorphism of drug oxidation in man [proceedings].
    Br J Pharmacol. 1979 Jul;66(3):430P-431P PMID: 526719
  73. Genetic control of drug levels in man: antipyrine.
    Science. 1968 Jul 5;161(3836):72-3 PMID: 5690279
  74. Anomalous results of studies on drug interaction in man. II. Halofenate (mk-185) and antipyrine, bishydroxycoumarin, and warfarin.
    Pharmacology. 1975;13(2):112-27 PMID: 49900
  75. Intrasubject variation in elimination half-lives of drugs which are appreciably metabolized.
    J Pharmacokinet Biopharm. 1973 Apr;1(2):165-73 PMID: 4797185
  76. Interindividual and intraindividual variations in aryl hydrocarbon hydroxylase in monocytes from monozygotic and dizygotic twins.
    Cancer Res. 1977 Nov;37(11):3904-11 PMID: 561657
  77. Genetic variation of aryl hydrocarbon hydroxylase in human lymphocytes.
    Am J Hum Genet. 1973 May;25(3):327-31 PMID: 4704864
  78. Elimination of antipyrine from saliva as a measure of metabolism in man.
    Clin Pharmacol Ther. 1975 Sep;18(3):249-58 PMID: 1164815
  79. Polymorphic hydroxylation of Debrisoquine in man.
    Lancet. 1977 Sep 17;2(8038):584-6 PMID: 71400
  80. Total body water in children.
    Pediatrics. 1951 Mar;7(3):321-7 PMID: 14827634
  81. The fate of antipyrine in man.
    J Pharmacol Exp Ther. 1950 Jan;98(1):97-104 PMID: 15403625
  82. Deficient metabolism of debrisoquine and sparteine.
    Clin Pharmacol Ther. 1980 Apr;27(4):547-9 PMID: 7357813
  83. Antipyrine metabolism in man: influence of age, alcohol, caffeine, and smoking.
    Clin Pharmacol Ther. 1975 Oct;18(4):425-32 PMID: 1164824
  84. Influence of the genetically controlled deficiency in debrisoquine hydroxylation on antipyrine metabolite formation.
    Pharmacology. 1981;22(6):349-58 PMID: 7267701
  85. Factors affecting antipyrine metabolism in West African villagers.
    Clin Pharmacol Ther. 1976 Sep;20(3):369-76 PMID: 954356
  86. Prediction of maintenance dose required to attain a desired drug concentration at steady-state from a single determination of concentration after an initial dose.
    Clin Pharmacokinet. 1980 Jul-Aug;5(4):377-85 PMID: 7398172
  87. Correlation of the plasma elimination of antipyrine and the appearance of 4-hydroxy antipyrine in the urine of man.
    Biochem Pharmacol. 1974 Jan 15;23(2):197-201 PMID: 4813341
  88. Diphenylhydantoin half-life in man and its inhibition by phenylbutazone: the role of genetic factors.
    Acta Med Scand. 1973 Jun;193(6):561-4 PMID: 4738705
  89. INSUFFICIENT PARAPHYDROXYLATION AS A CAUSE OF DIPHENYLHYDANTOIN TOXICITY.
    Neurology. 1964 Jun;14:542-8 PMID: 14161752
  90. A sensitive gas-chromatographic assay using a nitrogen-phosphorus detector for determination of antipyrine and aminopyrine in biological fluids.
    Pharmacology. 1979;19(5):228-36 PMID: 538077
  91. Dietary patterns and diurnal variations in aminopyrine disposition.
    Clin Pharmacol Ther. 1981 Jan;29(1):65-73 PMID: 7193105
  92. Implications of enzyme induction in drug toxicity studies.
    Toxicol Appl Pharmacol. 1967 Mar;10(2):340-51 PMID: 4962253
  93. Pharmacokinetics and metabolism of antipyrine (phenazone) after intravenous and oral administration.
    Arzneimittelforschung. 1982;32(5):575-8 PMID: 7201837
  94. The biotransformation of ethyl biscoumacetate (tromexan) in man, rabbit and dog.
    J Pharmacol Exp Ther. 1953 May;108(1):33-41 PMID: 13053419
  95. Effect of charcoal-broiled beef on antipyrine and theophylline metabolism.
    Clin Pharmacol Ther. 1978 Apr;23(4):445-50 PMID: 630792
  96. Genetic control of the phenobarbital-induced shortening of plasma antipyrine half-lives in man.
    J Clin Invest. 1969 Dec;48(12):2202-9 PMID: 5389794
  97. Genetic study of amobarbital elimination based on its kinetics in twins.
    Clin Pharmacol Ther. 1976 Dec;20(6):701-14 PMID: 1033050
  98. Elimination of antipyrine and benzo[a]pyrene metabolism in cultured human lymphocytes.
    Clin Pharmacol Ther. 1976 Jul;20(1):72-80 PMID: 1277727
  99. Influence of dietary protein and carbohydrate on antipyrine and theophylline metabolism in man.
    Clin Pharmacol Ther. 1976 Dec;20(6):643-53 PMID: 991535
  100. Effect of age and sex on human drug metabolism.
    Br Med J. 1971 Sep 11;3(5775):607-9 PMID: 5569980
  101. Steady-state plasma levels of nortriptyline in twins: influence of genetic factors and drug therapy.
    Br Med J. 1969 Dec 27;4(5686):764-8 PMID: 5391106
  102. Pharmacogenetics.
    Pediatr Clin North Am. 1972 Feb;19(1):21-36 PMID: 4558885
  103. Influence of DH/DL alleles regulating debrisoquine oxidation on phenytoin hydroxylation.
    Clin Pharmacol Ther. 1981 Apr;29(4):493-7 PMID: 7471615
  104. Antipyrine metabolism in the rat by three hepatic monooxygenases.
    Life Sci. 1980 Jun 9;26(23):1977-83 PMID: 7401910
  105. The physiological disposition of phenylbutazone (butazolidin) in man and a method for its estimation in biological material.
    J Pharmacol Exp Ther. 1953 Nov;109(3):346-57 PMID: 13109696
  106. Twin studies in pharmacogenetics.
    Hum Genet Suppl. 1978;(1):19-30 PMID: 285030
Article Info
Journal
Clinical pharmacokinetics
Abbr.
Clin Pharmacokinet
ISSN
0312-5963
DOI
10.2165/00003088-198308050-00002
Published
1983-00-00
Pages
378-409
Language
English
Region
Switzerland
NLM ID
7606849
Subset
IM
Grants
PHS HHS · MS26,027 · United States
External Links
PubMed source DOI: 10.2165/00003088-198308050-00002 View journal details
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