Basic pharmacological principle| Volume 29, SUPPLEMENT 1, 3-15, 1983

Variability in the human drug response

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      Variations in response to drugs may be pharmacodynamic, implying inter-individual differences in the response of receptors in equal concentrations of drug, or pharmacokinetic, implying that individuals receiving the same dose of drug will have different concentrations of drug in their body fluids. Either type of variation can be inherited or acquired. Variations in receptor sensitivity do occur but few instances, inherited or acquired, have well documented clinical relevance. If the dose response relationship for the drug in question is not steep, or if the therapeutic index is low, drug concentration in the region of the receptor will not be critical and causes of kinetic variation are unlikely to be clinically significant. However, it is the many causes of kinetic variation which are best described. These include effects due to drug formulation and changes in the absorption, distribution, metabolism and excretion of drugs. If a consideration of dynamics suggests that drug concentration will determine therapeutic efficacy, analysis and prediction of variability due to these factors is desirable. Prediction requires an accurate description of the system but commonly used pharmacokinetic models may fail when prediction is a goal. The variables, volume of distribution (Vd) and rate constant of elimination (Ke) are hybrid in that they arise from the interaction of patient and drug characteristics. Important events including macromolecular binding and altered blood flow may not be represented. More data is required to determine the clinical significance of pharmacodynamic variation but better analytical tools are required to deal with kinetic variation when this is important. Specifically, pharmacokinetic models should represent physiological variables and levels of unbound drug in body fluids should receive greater emphasis.


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        • O'Reilly R.A.
        • Aggeler P.M.
        • Hoag M.S.
        • Leong L.S.
        • Kropatkin M.L.
        Hereditary transmission of exceptional resistance to coumarin anticoagulant drugs: First reported kindred.
        N. Engl. J. Med. 1964; 271: 809-815
        • Breckenridge A.
        Oral anticoagulant drugs: pharmacokinetic aspects.
        in: 6th Edition. Seminars in Hematol.15. 1978: 19-26
        • Triggle D.J.
        in: Lamble J.W. Towards Understanding Receptors. Elsevier/North-Holland Biomedical Press, United Kingdom1981: 28-34
        • Simon E.J.
        Opiate receptors: some recent developments.
        in: Lamble J.W. Towards Understanding Receptors. Elsevier/North-Holland Biomedical Press, United Kingdom1981: 159-165
        • Shaw T.R.D.
        • Howard M.R.
        • Hamer J.
        Variation in the biological availability of digoxin.
        Lancet. 1972; (Aug. 12): 303-307
        • Kalowski S.
        • Radford N.
        • Kincaid-Smith P.
        Crystalline and macrocrystalline nitrofurantoin in the treatment of urinary tract infection.
        N. Engl. J. Med. 1974; 290: 385-387
        • Brodie B.B.
        Physico-chemical factors in drug absorption.
        in: Binns T.B. Absorption and Distribution of Drugs. E. & S. Livingstone Ltd, Edinburgh & London1964: 16-48
        • Dawes C.P.
        • Kendall M.J.
        • Welling P.G.
        Bioavailability of conventional and slow-release oxprenolol in fasted and nonfasted individuals.
        Br. J. Clin. Pharmac. 1979; 7: 299-302
        • Welling P.G.
        Influence of food and diet on gastrointestinal drug absorption: a review.
        J. Pharmacokinet. Biopharm. 1977; 5: 291-334
        • Lindenbaum J.
        • Rund D.G.
        • Butler V.P.
        • Tse-Eng D.
        • Saha J.R.
        Inactivation of digoxin by the gut flora: reversal by antibiotic therapy.
        N. Engl. J. Med. 1981; 305: 789-794
        • Tuttle C.B.
        Intramuscular injections and bioavailability.
        Am. J. Hosp. Pharm. 1977; 34: 965-968
        • Cockshott W.P.
        • Thompson G.T.
        • Howlett L.J.
        • Seeley E.T.
        Intramuscular or intralipomatous injections.
        N. Engl. J. Med. 1982; 307: 356-358
        • Silverman W.A.
        • Andersen D.H.
        • Blanc W.A.
        • Crozier D.N.
        A difference in mortality rate and incidence of kernicterus among premature infants allotted to two prophylactic antibacterial regimens.
        Pediatrics. 1956; 18: 614-624
        • Christensen L.K.
        • Hansen J.M.
        • Kristensen M.
        Sulphaphenzole-induced hypoglycaemic attacks in tolbutamide-treated diabetics.
        Lancet. 1963; II: 1298-1301
        • Sellers E.M.
        • Koch-Weser J.
        Potentiation of warfarin-induced hypoprothrombinemia by chloral hydrate.
        N. Engl. J. Med. 1970; 283: 827-831
        • Brodie V.B.
        • Hogben C.A.M.
        Some physico-chemical factors in drug action.
        J. Pharm. Pharmacol. 1957; 9: 345-380
        • Grausz H.
        • Schmid R.
        Reciprocal relation between plasma albumin level and hepatic sulfobromophthalein removal.
        N. Engl. J. Med. 1971; 284: 1403-1406
        • Weisiger R.
        • Gollan J.
        • Ockner R.
        Receptor for albumin on the liver cell surface may mediate uptake of fatty acids and other albumin-bound substances.
        Science. 1981; 211: 1048-1951
        • Piafsky K.M.
        • Borga O.
        • Odar-Cederlof I.
        • Johansson C.
        • Sjoqvist F.
        Increased plasma protein binding of propranolol and chlorpromazine mediated by disease-induced elevations of plasma alpha-1 acid glycoprotein.
        N. Engl. J. Med. 1978; 299: 1435-1439
        • Subbarao K.
        • Rucinski B.
        • Rausch M.A.
        • Schmid K.
        • Niewiarowski S.
        Binding of dipyridamole to human platelets and to alpha-1 acid glycoprotein and its significance for the inhibition of adenosine uptake.
        J. Clin. Invest. 1977; 60: 936-943
        • Reidenberg M.M.
        • Odar-Cederlof I.
        • Von Bahr C.
        • Borga O.
        • Sjoqvist F.
        Protein binding of diphenylhydantoin and desmethylimipraine in plasma from patients with poor renal function.
        N. Engl. J. Med. 1971; 285: 265-267
        • Hager W.D.
        • Fenster P.
        • Mayersohn M.
        • Perrier D.
        • Graves P.
        • Marcus F.I.
        • Goldman S.
        Digoxin-quinidine interaction.
        in: Pharmacokinetic evaluation. 6th Edition. N. Eng. J. Med.300. 1979: 1238-1241
        • Wilkinson G.R.
        • Shand D.G.
        A physiological approach to hepatic drug clearance.
        Clin. Pharmac. Ther. 1975; 18: 377-390
        • Rowell L.B.
        Human cardiovascular adjustments to exercise and thermal stress.
        Physiol. Rev. 1974; 54: 75-159
        • Sweeney G.D.
        Drugs - some basic concepts.
        Med. & Sci. in Sports & Exercise. 1981; 13: 247-253
        • Fine A.
        • Churchill D.N.
        Potentially lethal interaction of cimetidine and morphine.
        Can. Med. Assoc. J. 1981; 124: 1434-1435
        • Fenje P.C.
        • Isles A.F.
        • Baltodano A.
        • MacLeod S.M.
        • Soldin S.
        Interaction of cimetidine and theophylline in two infants.
        Can. Med. Assoc. J. 1982; 126: 1178-1179
        • Kerley B.
        • Ali M.
        Cimetidine potentiation of warfarin action.
        Can. Med. Assoc. J. 1982; 126: 116-117
        • Feely J.
        • Wilkinson G.R.
        • Wood A.J.J.
        Reduction of liver blood flow and propranolol metabolism by cimetidine.
        N. Engl. J. Med. 1980; 304: 692-695
        • Jackson J.E.
        Reduction of liver blood flow by cimetidine.
        N. Engl. J. Med. 1981; 305: 99-100
        • Eichelbaum M.
        Polymorphism of drug oxidation in man: novel findings.
        Trends in Pharm. Sci. 1981; 2: 31-34
        • Conney A.H.
        Pharmacological implications of microsomal enzyme induction.
        Pharmacol. Rev. 1967; 19: 317-366
        • Ruffalo R.L.
        • Thompson J.R.
        Effect of cimetidine on the clearance of benzodiazepines.
        N. Engl. J. Med. 1980; 303: 753-754
        • Weinberger M.M.
        • Smith G.
        • Milavetz G.
        • Hendeles L.
        Decreased theophylline clearance due to cimetidine.
        N. Engl. J. Med. 1981; 304: 670-671
        • Feely J.
        • Wilkinsn G.R.
        • Woods A.J.J.
        Reduction of liver blood flow and propranolol metabolism by cimetidine.
        N. Engl. J. Med. 1981; 304: 692-695
        • Graham C.F.
        • Turner W.M.
        • Jones J.K.
        Lidocaine-propranolol interactions.
        N. Engl. J. Med. 1981; 304: 1301
        • Kimberly R.P.
        • Plotz P.H.
        Aspirin-induced depression of renal function.
        N. Engl. J. Med. 1977; 297: 418-424
        • Greenblatt C.J.
        • Koch-Weser J.
        Clinical pharmacokinetics.
        N. Engl. J. Med. 1975; 293: 702-705
        • Bloch R.
        • Sweeney G.
        • Ahmed K.
        • Dickinson C.J.
        • Ingram D.
        ‘MacDope’: a simulation of drug disposition in the human body: applications in clinical pharmacokinetics.
        Br. J. Clin. Pharmac. 1980; 10: 591-602
        • Harrison L.I.
        • Gibaldi M.
        A physiologically based pharmacokinetic model for digoxin distribution and elimination in the rat.
        J. Pharm. Sci. 1977; 66: 1138-1142