Thomas A. Ban
Neuropsychopharmacology in Historical Perspective
Education in the Field in the Post-Neuropsychopharmacology Era
Background to An Oral History of the First Fifty Years
Special Areas (Volume Seven): 4. Pharmacokinetics
(Bulletin 62)

Pharmacodynamics deals with action of a substance on the body, whereas pharmacokinetics deals with the action of the body on the substance. Pharmacodynamic properties are responsible for the differential effect of a psychotropic drug in different psychiatric diagnoses, whereas pharmacokinetic properties for the differential effect of the same drug within a particular diagnosis.

The term pharmacokinetics was introduced by F.H. Dott in 1953 (Dott 1953; Waner 1981). A couple of years later Bernard Brodie and his associates revealed that the main pathways used by the organism for metabolizing drugs are: (1) oxidation by microsomal enzymes in the liver, (2) other oxidative reactions, such as dehydrogenation, oxidative deamination, (3) reduction reactions, (4) O-methylation, (5) hydrolysis (of esters and amides) and (6) conjugation (Brodie, Axelrod, Cooper et al. 1955; Brodie and Maickel 1958). By the end of the 1950s it was shown that oxidation by microsomal enzymes was the main pathway in the metabolism of lysergic acid diethylamide (LSD), a “psychotomimetic” substance, and that N-demethylation, partial oxidation of the sulfur atom, and glucuronide formation were the main pathways in the metabolism of chlorpromazine, the first therapeutically effective “antipsychotic” drug (Axelrod, Brady and Witkop 1957; Rothlin 1956). It was also recognized that the metabolic degradation of imipramine, the first therapeutically effective tricyclic antidepressant drug is similar to that of chlorpromazine (Fishman and Goldenberg 1960; Hermann, Schindler and Pulver 1959; Sourkes 1982).

Introduction of flame photometry by Victor Wynn rendered the measurement of plasma lithium levels feasible (Noack and Trautner 1953; Wynn 1950). The first clinical studies with lithium plasma level monitoring were conducted in the 1950s by Trautner and his associates, and by Schou and his associates (Fawcett and Wynn 1956; Johnson and Gershon 1999; Noack and Trautner 1953; Schou, Juel-Nielsen, Strömgren and Voldby 1954; Wynn 1950). It was in those early studies that the “therapeutic window” of lithium was detected by Trautner and his group.

The first plasma level determination of chlorpromazine was reported by Curry and Brodie in 1967 and of imipramine by Moody and his associates in the same year (Curry and Brodie 1967; Moody, Trait and Todrick 1967).

References:

Axelrod J, Brady RO, Witkop B, Evarts EV. The distribution and metabolism of lysergic acid

diethylamide. Annals NY Acad Sci 1957; 66: 435- 44.

Brodie BB, Axelrod J, Cooper JR, Gaudette L, LaDu BN, Mitoma C, Udenfriend S. Detoxication of drugs and other compounds by liver microsomes. Science 1955; 121: 603-4

Brodie BB, Maickel RP. Termination of drug metabolism.  Federation Proceedings 1958; 17: 1163-4.

Curry SH, Brodie BB. Estimation of nanogram quantities of chlorpromazine (CPZ) in plasma using gas liquid chromatography (GLC) and an electron capture detector. Federation Proceeding1967; 26: 761-2.

Dott FH. Der Blutspiegel-Kinetic der Konzentrationsabläufe in der Krieslauffűsigkeit. Leipzig: Thieme; 1953.

Fawcett JK, Wynn V. Variations of plasma electrolytes and total protein levels in the individual. BMJ 1956; 2: 282-5.

Fishman V, Goldenberg H.  Metabolism of chlorpromazine. Organic extractable fraction from human urine.  Proc Soc Exp Biol Med 1960; 104:  99 - 103.

Hermann B, Schindler W, Pulver R. Paperechromatographischer Nachweis von Stofffwechsel production des Tofranil. Med exp (Basel) 1959; 1: 381-5. 

Johnson G, Gershon S. Early North American research on lithium. Australian and New Zealand Journal of Psychiatry 1999; 33(supplement 1): 48-53.

Moody JC, Trait AC, Todrick A. Plasma levels of imipramine and desmethylimipramine during drug therapy. The British Journal of Psychiatry 1967; 113: 183-93. 

Noack CH, Trautner EM. The lithium treatment of maniacal psychosis. Med J Aust 1951; 38: 219-22.

Norman TR, Burrows GD. Measurement and pharmacokinetics of lithium. In: Burrows GD, Norman TR, Davies B, editors. Antimanics, Anticonvuksants and Other Drugs in Psychiatry. Amsterdam: Elsevier; 1987. p. 3-20.

Rothlin E. Metabolism of lysergic acid. Nature 1956; 173: 1400-1.

Schou M, Juel-Nielsen N, Strömgren E, Voldby H. The treatment of manic psychosis by the administration of lithium salts. J Neurol Neurosurg Psychiatry 1954; 17: 250-60. 

Sourkes TL.  Biochemistry of Mental Illness. New York: Hoeber Medical Division Harper and Row Publishers; 1962. p. 372-85.

Waner J. History of pharmacokinetics. Pharm Ther 1981; 12: 537-62.

Wynn V. Osmolarity disorders of the body fluids. Postgraduate Medical Journal 1950; 36: 70-119.

March 21, 2019