Drug action metabolism

T. A. Baillie, K. M. Schultz, Stereochemistry in the Drug Development Process Role of Chirality as a Determinant of Drug Action, Metabolism, and Toxicity in Ref. 92, pp. 21-43. 

Baillie, T.A. Schultz, K.M. Stereoselectivity in the drug development process role of chirality as a determinant of drug action, metabolism and toxicity. In The Impact of Stereochemistry on Drug Development and Use Aboul-Enein, H.Y., Wainer, I.W., Eds. John Wiley New York, 1997 21-43. 

In some cases the unwanted enantiomer can perturb other biological processes and cause catastrophic side effects. The use of enantiomerically pure compounds thus permits more specific drug action and the reduction in the amount of drug administered. Even in the cases where the other enantiomer is inactive, the work involved in its metabolism before secretion can be avoided. 

While the exact mechanism of action of procarbazine is unknown, it does inhibit DNA, RNA, and protein synthesis. The pharmacokinetics have never been fully characterized, but it is known that the drug is metabolized extensively. Procarbazine is used most often in the treatment of lymphoma. 

The terminator of drug action is, of course, elimination. Elimination is a composite of excretion (kidney, etc.) and biotransformation (metabolism). The primary measure of drug elimination from the whole body is clearance, CLt, defined as the volume of plasma fluid removed of drug per unit time. It is a direct measure of the loss of the drug from the system and can be calculated from Eq. (3.5) after IV administration of a dose of the drug. 

Apart from patient-specific parameters, external factors - most importantly the concomitant uptake of certain other chemicals present in diet, environment and especially other drugs - influence drug actions. Possible effects are manifold and can affect all stages of pharmacokinetic and pharmacodynamic processes in the body. Also direct interaction and inactivation of concomitantly administered substances are possible. Drug-drug interactions via modulation of metabolism present a very hot topic in pharmaceutical research and drug design. 

Cysteine-S-conjugates have also been proposed as kidney-selective pro-drugs. Renal metabolism of S-6-(purinyl)-L-cysteine resulted in the formation of 6-mercaptopurine by the action of P-lyase [51]. However, besides formation of the intended parent compound, other S-conjugates may be formed by various radical reactions, which may induce renal toxicity. 

The enzymatic conversion of many analogues of the naturally occurring purines directly to their biologically active form, the ribonucleotides, in vivo [5, 8, 10, 13, 39] underlines the importance of these enzymes to the drug action of this class of compounds. 2-Aminoadenine (2, 6-diaminopurine, I) [107], 2-fluoroadenine (II) [108], 4-aminopyrazolo [3, 4-d] pyrimidine (VIll) [109]. and 2- and 8-aza-adenine (IX and X) [ 110, 111] have all been shown to be substrates for the adenine phosphoribosyltransferase [J12, 113]. Extensive studies on the metabolism of 2-aminoadenine (I) in E. coli [114, 115], L cells [116], and mice [117] have also shown its conversion by this enzyme to the ribonucleotide. 

Folic acid derivatives are essential for DNA synthesis, in that they are cofactors for certain reactions in purine and pyrimidine biosynthesis, including the uracil-thymine methylation just described. They are also cofactors for several reactions relating to amino acid metabolism. The folic acid system thus offers considerable scope for drug action. 

Pharmacology The proposed mechanism of action of methyidopa is probably due to the drug s metabolism to alpha-methyl norepinephrine, which lowers arterial pressure by the stimulation of central inhibitory -adrenergic receptors, false neurotransmission or reduction of plasma renin activity. 

Excretion, along with metabolism and tissue redistribution, is important in determining both the duration of drug action and the rate of drug elimination. Excretion is a process whereby drugs are transferred from the internal to the external environment, and the principal organs involved in this activity are the kidneys, lungs, biliary system, and intestines. 

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