Abstract
A modern view of pharmacokinetics must include both linear and nonlinear systems. Evidence of nonlinearities in pharmacokinetics go back to the early 1930's with the origination of the concept that ethyl alcohol is eliminated at a fixed rate independent of its concentration in the body. This paper contains references to over 160 articles which suggest evidence on nonlinearities in drug absorption, distribution, metabolism and excretion, and the pharmacokinetics of drug action. These works are reviewed in a format of six tables: Evidence for Nonlinearities in Drug Absorption; Drug Distribution; Drug Metabolism; Renal Excretion of Drugs and Metabolites; Biliary Excretion of Drugs; and Pharmacokinetics of Drug Action. Special attention is given to the equations used to describe nonlinear kinetics, the recognition of nonlinearities, nonlinear models, and the fitting of data. Seven guidelines are presented for use in possible future pharmacokinetic studies involving drug kinetics.
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References
E. Widmark and J. Tandberg. Uber die Bedingungen fur die Akkumulation indifferenter narkoliken theoretische Bereckerunger.Biochem. Z. 147: 358–369 (1924).
T. Teorell. Kinetics of distribution of substances administered to the body. I. The extra-vascular modes of administration.Arch. Int. Pharmacodyn. 57: 205–225 (1937).
T. Teorell. Kinetics of distribution of substances administered to the body. II. The intra-vascular modes of administration.Arch. Int. Pharmacodyn. 57: 226–240 (1937).
E. Krüger-Thiemer. Nonlinear dose-concentration relationship.Il Farmao (Pavia) Ed. Sci. 23: 717–756 (1968).
L. Z. Benet and J. S. Turi. Use of general partial fraction theorem for obtaining inverse Laplace transforms in pharmacokinetic analysis.J. Pharm. Sci. 60: 1593–1594 (1971).
L. Z. Benet. General treatment of linear mammillary models with elimination from any compartment as used in pharmacokinetics.J. Pharm. Sci. 61: 536–541 (1972).
E. Widmark. Verteilung und Umwandlung des Äthylalkohols im Organismus des Hundes.Biochem. Z. 267: 128–134 (1933).
E. Widmark. Der Einfluss der Nahrungsbestandteile auf den Alkoholgehalt des Blutes.Biochem. Z. 267: 135–142 (1933).
J. G. Wagner and J. A. Patel. Variations in absorption and elimination rates of ethyl alcohol in a single subject.Res. Commun. Chem. Pathol. Pharm. 4: 61–76 (1972).
W. Wilbrandt and P. Rosenberg. The concept of carrier transport and its corollaries in pharmacology.Pharmacol. Rev. 13: 109–183 (1961).
C. S. Patlak. Contributions to the theory of active transport. III. The effect of drugs on active transport systems.Bull. Math. Biophys. 23: 173–195 (1961).
G. Levy and W. J. Jusko. Factors affecting the absorption of riboflavin in man.J. Pharm. Sci. 55: 285–289 (1966).
H. Ochsenfahrt and D. Winne. Intestinal blood flow and drug absorption from the rat jejunum.Life Sci. 7: 493–498 (1968).
M. Rowland, S. Riegelman, and W. L. Epstein. Absorption kinetics of griseofulvin in man.J. Pharm. Sci. 57: 984–989 (1968).
G. W. Hepner, C. C. Booth, J. Cowan, A. V. Hoffbrand, and D. L. Mollin. Absorption of crystalline folic acid in man.Lancet, Aug. 10, pp. 302–306 (1968).
W. B. Strum, P. F. Nixon, H. J. Binder, and J. R. Bertino. Intestinal absorption of 5-methyltetrahydrofolate (MTHF).Clin. Res. 18: 389 (1970) (abst.).
F. Lauterback. Comparison of intestinal penetration of cortisol and conuallatexin: Demonstration of a transport mechanism for cariotonic steroids.Biochim. Biophys. Acta 150: 146–155 (1968).
K. Kakemi, T. Arita, R. Hori, R. Konishi, and K. Nishimura. Absorption and excretion of drugs. XXXIII. The correlation between the absorption of barbituric acid derivatives from the rat small intestine and their binding to the mucosa.Chem. Pharm. Bull. (Tokyo) 17: 248–254 (1969).
A. Suzuki, W. I. Higuchi, and N. F. H. Ho. Theoretical model studies of drug absorption and transport in the gastrointestinal tract. I.J. Pharm. Sci. 59: 651–659 (1970).
W. Crouthamel, J. T. Doluisio, R. E. Johnson, and L. Diamond. Effect of mesenteric blood flow on intestinal drug absorption.J. Pharm. Sci. 59: 878–879 (1970).
D. Winne. Formal kinetics of water and solute absorption with regard to intestinal blood flow.J. Theoret. Biol. 27: 1–18 (1970).
P. Lauger and G. Stark. Kinetics of carrier-mediated ion transport across lipid bilayer membranes.Biochim. Biophys. Acta 211: 458–466 (1970).
C. McMartin and P. Simpson. The absorption and metabolism of guanethidine in hypertensive patients requiring different doses of the drug.Clin. Pharmacol. Therap. 12: 73–77 (1971).
J. C. Dearden and E. Tomlinson. Buccal absorption as a parameter of analgesic activity of somep-substituted acetanilides.J. Pharm. Pharmacol. 23: 73S-76S (1971) (suppl.).
T. Fuwa, T. Iga, M. Nakano, H. Nogami, and K. Kashima. Biopharmaceutical studies on indomethacin. II. Mechanism of intestinal absorption of indomethacin in ratin vitro and availability of micronized powder after oral administration in man.J. Pharm. Soc. Japan 91: 1223–1227 (1971).
R. B. Smith, L. W. Dittert, W. O. Griffen, Jr., and J. T. Doluisio. Pharmacokinetics of pentobarbital after intravenous and oral administration.J. Pharmacokin. Biopharm. 1: 5–16 (1973).
J. G. Wagner and A. J. Sedman. Quantitation of rate of gastrointestinal and buccal absorption of acidic and basic drugs based on extraction theory.J. Pharmacokin. Biopharm. 1: 23–50 (1973).
W. H. Barr and S. Riegelman. Intestinal drug absorption and metabolism. I. Comparison of methods and models to study physiological factors ofin vitro andin vivo intestinal absorption.J. Pharm. Sci. 57: 154–163 (1970).
W. H. Barr and S. Riegelman. Intestinal drug absorption and metabolism. II. Kinetic aspects of intestinal glucuronide conjugation.J. Pharm. Sci. 59: 164–168 (1970).
J. A. Jacquez, R. Bellman, and R. Kalaba. Some mathematical aspects of chemotherapy. II. The distribution of a drug in the body.Bull. Math. Biophys. 22: 309–322 (1960).
L. A. Carlson and D. Hallberg. Studies on the elimination of exogenous lipids from the blood stream. The kinetics of the elimination of a fat emulsion and of chylmicrones in the dog after a single injection.Acta. Physiol. Scand. 59: 52–61 (1963).
D. Hallberg. Studies on the elimination of exogenous lipids from the blood stream. The kinetics of the elimination of a fat emulsion studied by a constant infusion technique in man.Acta Physiol. Scand. 64: 299–305 (1965).
D. Hallberg. Studies on the elimination of exogenous lipids from the blood stream. The kinetics of the elimination of a fat emulsion studied by single injection technique in man.Acta Physiol. Scand. 64: 306–313 (1965).
E. Andersson, B. Norberg, and A. C. Teger-Nilsson. On the import of the clinical determination of the so-called hepatic mass (hm) with bromsulfalein.Scand. J. Clin. Lab. Invest. 15: 517–522 (1963).
C. A. Goresky. Initial distribution and rate of uptake of sulfobromophthalein in the liver.Am. J. Physiol. 207: 13–26 (1964).
K. Winkler and N. Tygstrup. The day-to-day variations in bromsulfalein elimination curves.Scand. J. Clin. Lab. Invest. 16: 481–490 (1964).
B. H. Marks, S. Dutta, J. Gauthier, and D. Elliott. Distribution in plasma, uptake by the heart and excretion of ouabain-H3 in human subject.J. Pharmacol. Exptl. Therap. 145: 351–356 (1964).
L. S. Schanker and A. S. Morrison. Physiological disposition of guanethidine in the rat and its uptake by heart slices.Internat. J. Neuropharmacol. 4: 23–39 (1965).
E. S. Henderson, R. H. Adamson, C. Denham. and V. T. Oliverio. The metabolic fate of tritiated methotrexate. I. Absorption, excretion, and distribution in mice, rats, dogs and monkeys.Cancer Res. 25: 1008–1018 (1965).
D. S. Zaharko, R. L. Dedrick, and V. T. Oliverio. Time and dose dependent tissue concentration of methotrexate.Fed. Proc. 29: 932 (1970) (abst.).
K. G. Bischoff, R. L. Dedrick, D. S. Zaharko, and J. A. Longstreth. Methotrexate pharma-cokinetics.J. Pharm. Sci. 60: 1128–1133 (1971).
H. Stupp, S. Ruck, H. Sous. J. P. Brun, and F. Legier. Kanamycin dosage and levels in ear and other organs.Arch. Ololaryngol. 86: 515–521 (1967).
S. D. Sholkoff, E. J. Eyering, M. Rowland, and S. Riegelman. Plasma and synovial fluid concentrations of acetylsalicyclic acid in patients with rheumatoid arthritis.Arth. Rheum. 10: 348–351 (1967).
R. Nagashima, G. Levy, and E. Nelson. Comparative pharmacokinetics of coumarin anticoagulants. I. Unusual interaction of bishydroxycoumarin with plasma proteins— development of a new assay.J. Pharm. Sci. 57: 58–67 (1968).
R. Nagashima, G. Levy, and E. J. Sarcione. Comparative pharmacokinetics of coumarin anticoagulants. III. Factors affecting the distribution and elimination of bishydroxycoumarin (BHC) in isolated liver perfusion studies.J. Pharm. Sci. 57: 1881–1888 (1968).
R. Nagashima, G. Levy, and R. A. O'Reilly. Comparative pharmacokinetics of coumarin anticoagulants. IV. Application of a three-compartmental model to the analysis of the dose-dependent kinetics of bishydroxycoumarin elimination.J. Pharm. Sci. 57: 1888–1895 (1968).
G. Levy and R. Nagashima. Comparative pharmacokinetics of coumarin anticoagulants. VI. Effect of plasma protein binding on the distribution and elimination of bishydroxy-coumarin by rats.J. Pharm. Sci. 58: 1001–1004 (1969).
W. H. Oldendorf. Dose-dependence of the rapid reappearance in blood of very small intravenous doses of Se75 Selenite.Internat. J. Appl. Radiation Isotopes 19: 411–414 (1968).
K. B. Bischoffand R. L. Dedrick. Thiopental pharmacokinetics.J. Pharm. Sci. 57: 1347–1357 (1968).
R. L. Dixon, E. S. Owens, and D. P. Rall. Evidence of active transplant of benzyl-14C-penicillin from cerebrospinal fluid to blood.J. Pharm. Sci. 58: 1106–1109 (1969).
P. F. Binnion, L. M. Morgan, H. M. Stevenson, and E. Fletcher. Plasma and myocardial digoxin concentrations in patients on oral therapy.Brit. Heart J. 31: 636–640 (1969).
G. Paumgartner, P. Probst, R. Kraines, and C. M. Leevy. Kinetics of indocyanine green removal from the blood.Ann. N.Y. Acad. Sci. 170: 134–147 (1970).
J. C. Drach, J. P. Howell, P. E. Borony, and A. J. Glazko. Species differences in the metabolism of diphenhydramine (Benadryl).Proc. Soc. Exptl. Biol. Med. 135: 849–853 (1970).
E. D. Rees, P. Mandelstram, J. Q. Lowry, and H. Lipscomb. A study on the metabolism of intestinal absorption of benzopyrene (BBA 75555).Biochim. Biophys. Ada 225: 96–107 (1971).
J. J. Timmes, N. J. Demos, and S. I. Chong. Lung tissue and serum levels of methacycline.Clin. Pharmacol. Therap. 12: 920–922 (1971).
A. R. DiSanto and J. G. Wagner. Pharmacokinetics of highly ionized drugs. I. Methylene blue—whole blood, urine and tissue assays.J. Pharm. Sci. 61: 598–602 (1972).
A. R. DiSanto and J. G. Wagner. Pharmacokinetics of highly ionized drugs. III. Methylene blue—blood levels in the dog and tissue levels in the rat following intravenous administration.J. Pharm. Sci. 61: 1090–1094 (1972).
R. G. Wiegand and A. H. C. Chun. Serum protein binding of erythromycin and erythromycin 2-propionate ester.J. Pharm. Sci. 61: 425–428 (1972).
D. S. Alberts, M. R. Bachur, and J. L. Holtzman. The pharmacokinetics of daunomycin in man.Clin. Pharmacol. Therap. 12: 96–104 (1971).
R. Nagashima and G. Levy. Effect of perfusion rate and distribution factors on drug elimination kinetics in a perfused organ system.J. Pharm. Sci. 57: 1991–1993 (1968).
J. B. Hill. The effect of altering blood pH on rat tissue and plasma salicylate concentrations.Fed. Proc. 29: 934 (1970) (abst.).
S. M. Somani, D. Schumacher, R. Thomson, and R. H. McDonald, Jr. Characterization of the distribution of secobarbital and its compartmental simulation.Fed. Proc. 30(2): 335 (1971) (abst.).
W. L. Chiou and S. Riegelman. Disposition kinetics of griseofulvin in dogs.J. Pharm. Sci. 58: 1500–1504 (1969).
L. E. Mather, G. J. Long, and J. T. Thomas. The intravenous toxicity and clearance of bupivacaine in man.Clin. Pharmacol. Therap. 12: 935–943 (1971).
M. Tomura and T. Akera. Relationship between dose and plateau levels of drugs eliminated by parallel first-order and capacity-limited kinetics.Jap. J. Pharmacol. 21: 682–685 (1971).
M. G. Eggleton. Some factors affecting the metabolic rate of alcohol.J. Physiol. (Lond.) 98: 239–254 (1940).
F. Lundquist and H. Wolthers. The kinetics of alcohol elimination in man.Acta Pharmacol. Toxicol. 14: 265–289 (1958).
H. G. Bray, W. V. Thorpe, and K. White. Kinetic studies of the metabolism of foreign organic compounds. I. The formation of benzoic acid from benzamide, toluene, benzyl alcohol and benzaldehyde and its conjugation with glycine and glucuronic acid in the rabbit.Biochem. J. 48: 88–96 (1951).
D. Schachter and J. G. Manis. Salicylate and salicyl conjugates. Fluorimetric estimation. Biosynthesis and renal excretion in man.J. Clin. Invest. 37: 800–807 (1958).
G. Levy. Salicylurate formation—Demonstration of Michaelis-Menten kinetics in man.J. Pharm. Sci. 54: 496 (1965).
G. Levy. Pharmacokinetics of salicylate elimination in man.J. Pharm. Sci. 54: 959–967 (1965).
E. Nelson, M. Hanano, and G. Levy. Comparative pharmacokinetics of salicylate elimination in man and rats.J. Pharmacol. Exptl. Therap. 153: 159–166 (1966).
G. Levy. Dose-dependent effects in pharmacokinetics. In D. H. Tedeschi and R. E. Tedeschi (eds.),Importance of Fundamental Principles in Drug Evaluation, Raven Press, New York. 1968. pp. 141–172.
G. Levy and S. J. Yaffe. The study of salicylate pharmacokinetics in intoxicated infants and children.Clin. Toxicol. 1: 409–424 (1968).
G. Levy, L. P. Amsel, and H. C. Elliott. Kinetics of salicyluric acid elimination in man.J. Pharm. Sci. 58: 827–829 (1969).
G. Levy, A. W. Vogel, and L. P. Amsel. Capacity-limited salicylurate formation during prolonged administration of aspirin to healthy human subjects.J. Pharm. Sci. 58: 503–504 (1969).
G. Levy and H. Yamada. Estimation of drug metabolite elimination kinetics in man by the synthesis-blocking method.J. Pharm. Pharmacol. 22: 964–965 (1970).
G. Levy, L. Weintraub, T. Matsuzawa, and S. R. Oles. Absorption metabolism and excretion of salicyl phenolic glucuronide in rats.J. Pharm. Sci. 55: 1319–1320 (1966).
G. Levy. Saturation of glucuronide formation in man and its clinical implications.Chem. Biol. Interactions 3: 291 (1971).
G. Levy, T. Tsuchiya, and L. P. Amsel. Limited capacity for salicyl phenolic glucuronide formation and its effect on the kinetics of salicylate elimination in man.Clin. Pharmacol. Therap. 13: 258–268 (1972).
G. Levy and L. P. Amsel. Kinetics of competitive inhibitions of salicylic acid conjugation with glycine in man.Biochem. Pharmacol. 15: 1033–1038 (1966).
G. Levy and J. A. Procknal. Drug biotransformation interactions in man. I. Mutual inhibition in glucuronide formation of salicylic acid and salicylamide in man.J. Pharm. Sci. 57: 1330–1334 (1968).
L. P. Amsel and G. Levy. Drug transformation interactions in man. II. A pharmaco-kinetic study of the simultaneous conjugation of benzoic and salicylic acids with glycine.J. Pharm. Sci. 58: 321–326 (1969).
P. Nordquist, J. G. Harthon, and R. Karlsson. Metabolic kinetics of salicylsalicylic acid, aspirin and sodium salicylate in man.Nord. Med. 74: 1024–1026 (1965).
G. Levy and T. Matsuzawa. Role of sulfate formation in biotransformation of salicylamide in man.J. Pharm. Sci. 55: 222–223 (1966).
G. Levy and T. Matsuzawa. Pharmacokinetics of salicylamide elimination in man.J. Pharmacol. Exptl. Therap. 156: 285–293 (1967).
W. H. Barr and S. Riegelman. Effect of capacity limited metabolism on plasma levels of free salicylamide in man. Presented to APhA Academy of Pharmaceutical Sciences, May 6, 1968, Miami Beach, Fla.
G. Levy and H. Yamada. Drug biotransformation interactions in man. III. Acetaminophen and salicylamide.J. Pharm. Sci. 60: 215–221 (1971).
G. Levy and G. C. Regardh. Drug biotransformation interactions in man. V. Acetaminophen and salicylic acid.J. Pharm. Sci. 60: 608–611 (1971).
K. Kakemi, T. Arita, H. Sezaki. and M. Nakano. Absorption and excretion of drugs. XVI. Inhibition of isoniazid acetylation by p-aminobenzaldehyde and its related compounds.J. Pharm. Soc. Japan 83: 260–263 (1963).
M. M. Drucker, S. H. Blondheim, and L. Wislicki. Factors affecting acetylationin vivo of para-aminobenzoic acid by human subjects.Clin. Sci. 26: 133–141 (1964).
P. G. Dayton, S. A. Cucinell, M. Weiss, and J. M. Perel. Dose-dependence of drug plasma level decline in dogs.J. Pharmacol. Exptl. Therap. 158: 305–316 (1967).
R. Nagashima. G. Levy, and N. Back. Comparative pharmacokinetics of coumarin anticoagulants. II. Pharmacokinetics of bishydroxycoumarin elimination in the rat, guinea pig, dog and rhesus monkey.J. Pharm. Sci. 57: 68–71 (1968).
R. Nagashima and G. Levy. Comparative pharmacokinetics of coumarin anticoagulants. III. Factors affecting the distribution and elimination of bishydroxycoumarin (BHC) in isolated liver perfusion studies.J. Pharm. Sci. 58: 845–849 (1969).
J. G. Wagner and R. E. Damiano. Relationship among area under serum concentration curve, dose, and half-life for novobiocin administered in combination with tetracycline.J. Clin. Pharmacol. J. New Drugs 8: 102–112 (1968).
A. A. Kondritzer, P. Zvirblis. A. Goodman, and S. H. Paplanus. Blood plasma levels and elimination of salts in 2-PAM in man after oral administration.J. Pharm. Sci. 57: 1142–1146 (1968).
F. R. Sidell, W. A. Groff, and R. I. Ellin. Blood levels of oxime and symptoms in humans after single and multiple oral doses of 2-pyridine aldoxime methochloride.J. Pharm. Sci. 58: 1093–1098 (1969).
J. W. Estes, E. W. Pelikan, and E. Krüger-Thiemer. A retrospective study of the pharmaco-kinetics of heparin.Clin. Pharmacol. Therap. 10: 329–337 (1969).
J. G. Wagner. Design and data analysis of biopharmaceutical studies in man.Can. J. Pharm. Sci. 1: 55–68 (1966).
J. T. Doluisio and L. W. Dittert. Dosing of tetracyclines on biologic half-life in serum.Clin. Pharmacol. Therap. 10: 690–701 (1969).
J. Shibasaki, T. Koizumi, and T. Tanaka. Drug absorption, metabolism and excretion. I. Some pharmacokinetic aspects of metabolism of acetanilide and 4-hydroxylacetanilide.Chem. Pharm. Bull. (Tokyo) 16: 1661–1673 (1968).
A. J. Glazko, T. Chang, J. Baukema, W. A. Dill, J. R. Goulet, and R. A. Buchanan. Metabolic disposition of diphenylhydantoin in normal human subjects following intravenous administration.Clin. Pharmacol. Therap. 10: 498–504 (1969).
T. Suzuki, Y. Saitoh, and K. Nishihara. Kinetics of diphenylhydantoin disposition in man.Chem. Pharm. Bull. (Tokyo) 18: 405–411 (1970).
M. Blum, I. McGilveray, C. Becker, and S. Riegelman. Clinical implications derived from pharmacokinetics of diphenylhydantoin (DPH).Clin. Res. 19: 121 (1971) (abst.).
K. Arnold and N. Gerber. The rate of decline of diphenylhydantoin in human plasma.Clin. Pharmacol. Therap. 11: 121–134 (1970).
N. Gerber and K. Arnold. Studies on the metabolism of diphenylhydantoin in mice.J. Pharmacol. Exptl. Therap. 167: 77–89 (1969).
N. Gerber, W. L. Weller, R. Lynn, R. E. Rangno, B. J. Sweetman, and M. T. Bush. Study of dose-dependent metabolism of 5,5-diphenylhydantoin in the rat using new methodology for isolation and quantitation of metabolitesin vivo andin vitro.J. Pharmacol. Exptl. Therap. 178: 567–579 (1971).
N. Gerber and J. G. Wagner. Explanation of dose-dependent decline of diphenylhydantoin plasma levels by fitting to the integrated form of the Michaelis-Menten equation.Res. Commun. Chem. Pathol. Pharm. 3: 445–466 (1972).
J. G. Wagner. Properties of the Michaelis-Menten equation and its integrated form which are useful in pharmacokinetics.J. Pharmacokin. Biopharm. 1: 103–121 (1973).
K. Balasubramaniam, G. E. Mawer, and P. J. Simons. The influence of dose on the distribution and elimination of amylobarbitone in healthy subjects.Brit. J. Pharmacol. 40: 578P-579P (1970).
G. H. Mudge and I. M. Weiner. Renal excretion of weak organic acids and bases. In C. A. M. Hogben (ed.),Drugs and Membranes, Vol. IV, pp. 157–164.
I. M. Weiner and G. H. Mudge. Renal tubular mechanisms for excretion of organic acids and bases.Am. J. Med. Sci. 36: 743–762 (1964).
I. M. Weiner, K. C. Blanchard, and G. H. Mudge. Factors influencing renal excretion of foreign organic acids.Am. J. Physiol. 207: 953–963 (1964).
I. M. Weiner, J. E. Glasser, and L. Lack. Renal excretion of bile acids:Taurocholic, glycocholic and cholic acids.Am. J. Physiol. 207: 964–970 (1964).
A. H. Beckett and M. Rowland. Rhythmic urinary excretion of amphetamine in man.Nature 204: 1203–1204 (1964).
K. C. Huang and D. S. T. Lin. Kinetic studies on transport of PAH and other organic acids in isolated renal tubules.Am. J. Physiol. 208: 391–396 (1965).
W. J. Jusko, G. Levy, S. Y. Yaffe, and R. Gorodescher. Effect of probenecid on renal clearance of riboflavin in man.J. Pharm. Sci. 59: 473–477 (1970).
W. J. Jusko, G. Levy, S. Y. Yaffe, and R. Gorodescher. Pharmacokinetic evidence for saturable renal tubular reabsorption of riboflavin.J. Pharm. Sci. 59: 765–772 (1970).
L. Dettli and P. Spring. Diurnal variations in the elimination rate of sulfonamide in man.Helv. Med. Acta 33: 291–306 (1966).
A. H. Beckett, R. N. Soyes, and G. T. Tucker. Use of the analogue computer to examine the quantitative relation between urinary pH and kidney reabsorption of drugs partially ionized at physiological pH.J. Pharm. Pharmacol. 20: 269–276 (1968).
A. H. Beckett, R. N. Boyes, and G. T. Tucker. Use of the analogue computer to predict the distribution and excretion of drugs under conditions of fluctuating urinary pH.J. Pharm. Pharmacol. 20: 277–282 (1968).
M. Pfeffer, J. M. Schor, S. Bolton, and R. Jacobson. Human urinary excretion of the quaternary ammonium compounds anisotropine methylbromide and propantheline bromide.J. Pharm. Sci. 57: 1375–1379 (1968).
J. Shibasaki, T. Koizumi, and W. Higuchi. Drug absorption, metabolism and excretion. IV. Pharmacokinetic studies on renal transport. I. Simultaneous chemical reaction and diffusion (SCRD) model for uphill transport.Chem. Pharm. Bull. (Tokyo) 16: 2273–2277 (1968).
J. Shibasaki, R. Konishi, Y. Takeda, and T. Koizumi. Drug absorption, metabolism and excretion. VII. Pharmacokinetics of formation and excretion of the conjugates ofN-acetyl-p-aminophenol in rabbits.Chem. Pharm. Bull. (Tokyo) 19: 1800–1808 (1971).
A. R. DiSanto and J. G. Wagner. Pharmacokinetics of highly ionized drugs. II. Methylene blue—absorption, metabolism, and excretion in man and dog after oral administration.J. Pharm. Sci. 61: 1086–1094 (1972).
J. B. Nagwekar and A. Unnikrishnan. Michaelis-Menten kinetics of renal tubular secretion of d-(—)-p-methyl mandelic acid and d-(—)-p-ethyl mandelic acid in rats.J. Pharm. Sci. 60: 375–380 (1971).
L. S. Schanker. Concentrative transfer of an organic cation from blood into bile.Biochem. Pharmacol. 11: 253–254 (1962).
L. J. Schoenfield, D. B. McGill, and W. T. Foulk. Studies of suifobromophthalein sodium (BSP) metabolism in man. III. Demonstration of a transport maximum (Tm) for biliary excretion of BSP.J. Clin. Invest. 43: 1424–1432 (1964).
R. T. Williams, P. Milburn, and R. L. Smith. The influence of enterohepatic circulation on toxicity of drugs.Ann. N.Y. Acad. Sci. 123: 110–124 (1965).
C. Lanman, S. Muranishi, and L. S. Schanker. Active transport of tetracycline into bile.Pharmacologist 12: 293 (1970) (abst.).
D. W. Yesair, M. Callahan, L. Remington, and C. J. Kensler. Role of the enterohepatic cycle of indomethacin on its metabolism, distribution in tissues and its excretion by rats, dogs and monkeys.Biochem. Pharmacol. 19: 1579–1590 (1970).
W. J. O'Reilly, P. A. Pitt, and A. J. Ryan. Pharmacokinetic model for the successive demethylation and biliary secretion of methyl orange in the rat.Brit. J. Pharmacol. 43: 167–179 (1971).
J. E. Axelson and M. Gibaldi. Absorption and excretion of riboflavin in the rat:An unusual example of nonlinear pharmacokinetics.J. Pharm. Sci. 61: 404–407 (1972).
J. G. Wagner. Kinetics of pharmacologic response. I. Proposed relationships between response and drug concentration in the intact animal and man.J. Theoret. Biol. 20: 173–201 (1968).
A. R. DiSanto and J. G. Wagner. Kinetics of pharmacologic response. II. Equation for turnover time of goldfish as a function of concentration of ethanol and a theoretical derivation based on a combination of occupation and rate receptor theories.J. Pharm. Sci. 58: 1077–1085 (1969).
M. Gibaldi and G. Levy. Dose-dependent decline of pharmacologic effects of drugs with linear pharmacokinetic characteristics.J. Pharm. Sci. 61: 567–569 (1972).
J. G. Wagner. Relations between drug concentration and response.J. Mondial de Pharmacie 14: 279–310 (1971).
G. Levy and M. Gibaldi. Pharmacokinetics of drug action.Ann. Rev. Pharmacol. 12: 85–98 (1972).
T. Tsuchiya and G. Levy. Relationship between dose and plateau levels of drugs eliminated by parallel first-order and capacity-limited kinetics.J. Pharm. Sci. 61: 541–544 (1972).
E. Krüger-Thiemer. Pharmacokinetics and dose-concentration relationships. In Proceedings of the Third International Pharmacological Meeting, Sao Paulo, 1966, Vol. 7:Physico-Chemical Aspects of Drug Actions, Pergamon Press, New York, 1968, pp. 63–113.
E. Krüger-Thiemer and R. Levine. The solution of pharmacological problems with computers. VIII. Non first-order models of drug metabolism.Arzneim.-Forsch. 18: 1575–1579 (1968).
P. A. Shore, B. B. Brodie, and C. A. M. Hogben. The gastric secretion of drugs; a pH partition hypothesis.J. Pharmacol. Exptl. Therap. 119: 361–369 (1957).
C. A. M. Hogben, D. J. Tocco, B. B. Brodie, and L. S. Schanker. On the mechanism of intestinal absorption of drugs.J. Pharmacol. Exptl. Therap. 125: 275–282 (1959).
A. Suzuki, W. I. Higuchi, and N. F. H. Ho. Theoretical model studies of drug absorption and transport in the gastrointestinal tract. II.J. Pharm. Sci. 59: 651–659 (1970)
L. Michaelis and M. L. Menten. Die Kinetic der Invertinwirkung.Biochem. Z. 49: 333–369 (1913).
A. Goldstein. Saturation of alcohol dehydrogenase by ethanol.New Engl. J. Med. 283: 875 (1970).
J. G. Wagner. A new generalized nonlinear pharmacokinetic model and its implications. InBiopharmaceutics and Relevant Pharmacokinetics, 1st ed., Drug Intelligence Publications, Hamilton, Ill., 1971, Chap. 40, pp. 302–317.
A. R. DiSanto and J. G. Wagner. Potential erroneous assignment of nonlinear data to the classical linear two-compartment open model.J. Pharm. Sci. 61: 552–555 (1972).
M. Rowland and S. Riegelman. Pharmacokinetics of acetylsalicylic acid and salicylic acid after intravenous administration in man.J. Pharm. Sci. 57: 1313–1319 (1968).
M. Rowland, L. Z. Benet, and S. Riegelman. Two-compartment model for a drug and its metabolite:Application to acetylsalicylic acid pharmacokinetics.J. Pharm. Sci. 59: 364–367 (1970).
J. P. Wagner. Fallacy in concluding there are zero order kinetics from blood level and urinary excretion data.J. Pharm. Sci. 56: 586–594 (1967).
J. G. Wagner. Pharmacokinetics.Ann. Rev. Pharmacol. 8: 67–93 (1968).
B. K. Martin. Potential effects of the plasma proteins on drug distribution.Nature 207: 274–276 (1965).
M. C. Meyer and D. E. Guttman. The binding of drugs by plasma proteins.J. Pharm. Sci. 57: 895–918 (1968).
J. J. Coffey, F. J. Bullock, and P. T. Schoenemann. Numerical solution of nonlinear pharmacokinetic equations; effects of plasma protein binding on drug distribution and elimination.J. Pharm. Sci. 60: 1623–1628 (1971).
S. H. Curry. Theoretical changes in drug distribution resulting from changes in binding to plasma proteins and to tissues.J. Pharm. Pharmacol. 22: 753–757 (1970).
E. Kruger-Thiemer, W. Diller, and P. Bunger. Pharmacokinetic models regarding protein binding of drugs.Antimicrob. Agents Chemotherap. (Wash.), pp. 183–191 (1965, 1966).
E. R. Reeve. The plasma albumin system:A first attempt at a kinetic description in dynamic clinical studies with radioisotopes. In Proceedings of a Symposium, Oak Ridge Institute of Nuclear Studies, 1963, U.S. Department of Commerce, TID 7678, Office of Technical Services, Washington, D.C., 1964, pp. 445–472.
J. M. Thorp. The influence of plasma proteins on the action of drugs. In T. B. Binns (ed.),Absorption and Distribution of Drugs, Williams and Wilkins, Baltimore, 1964, pp. 64–76.
J. R. Gillette. Factors affecting drug metabolism.Ann. N. Y. Acad. Sci. 179: 43–66 (1971).
R. L. Dedrick and K. B. Bischoff. Pharmacokinetics in applications of the artificial kidney.Chem. Engr. Prog. Symp. Ser. 64: 32–44 (1968).
K. B. Bischoff, R. L. Dedrick, and D. S. Zaharko. Preliminary model for methotrexate pharmacokinetics.J. Pharm. Sci. 59: 149–154 (1970).
A. R. DiSanto. A new nonlinear pharmacokinetic model with specific application to methylene blue. Ph.D. dissertation, University of Michigan, Ann Arbor, 1971.
M. Civen, B. M. Ulrich, B. M. Trimmer, and C. B. Brown. Circadian rhythms of liver enzymes and their relationship to enzyme induction.Science 157: 1563–1564 (1967).
F. M. Radzialowski and W. F. Bousquet. Circadian rhythm in hepatic drug metabolizing activity in the rat.Life Sci. 6: 2545–2548 (1967).
J. J. Burns and A. H. Conney. Enzyme stimulation and inhibition in the metabolism of drugs.Proc. Roy. Soc. Med. 58: 955–960 (1965).
G. L. Atkins. A versatile digital computer program for non-linear regression analysis.Biochim. Biophys. Acta 252: 405–420 (1971).
G. L. Atkins. Some applications of a digital computer program to estimate biological parameters by non-linear regression analysis.Biochim. Biophys. Acta 252: 421–426 (1971).
J. Buell and R. Kalaba. Quasilinearization and the Fitting of Nonlinear Models of Drug Metabolism to Experimental Kinetic Data, Technical Report USCEE-312, Electronic Sciences Laboratory, University of Southern California, Los Angeles, 1968.
A. J. Sedman and J. G. Wagner. Quantitative pooling of both parallel Michaelis—Menten formation equations and Langmuir-type equations for bindings of drugs to tissues. In Abstracts of Symposia and Contributed Papers Presented to the APhA Academy of Pharmaceutical Sciences at the 119th Annual Meeting of the American Pharmaceutical Association, Houston Texas, 1972, Vol. 2, No. 1, Abst. 16, p. 61.
G. Spears, J. G. T. Sneyd, and E. G. Loten. A method of deriving kinetic constants for two enzymes acting on the same substrate.Biochem. J. 125: 1149–1151 (1971).
J. L. Neal. Analysis of Michaelis kinetics for two independent saturable membrane transport functions.J. Theoret. Biol. 35: 113–118 (1972).
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Supported in part by Public Health Service Grant 5-P11-GM15559.
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Wagner, J.G. A modern view of pharmacokinetics. Journal of Pharmacokinetics and Biopharmaceutics 1, 363–401 (1973). https://doi.org/10.1007/BF01059664
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DOI: https://doi.org/10.1007/BF01059664