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The synthesis, high-performance liquid chromatographic and mass spectrometric analysis of N4-trideuteroacetylsulphamerazine is described. N4-trideuteroacetylsulphamerazine in man is deacetylated into sulphamerazine, which in turn is acetylated again into N4-acetylsulphamerazine. The existence of a deacetylationacetylation equilibrium in man has been demonstrated.

MANY BIOGENOUS SUBSTANCES and drugs exerting physiological and pharmacological effects are converted into metabolites with almost identical effects or into substances without any pharmacological activity. The plasma concentration time curve of a metabolite can be described by an equation of at least two e-functions: that of the formation (k m) and that of the elimination (k.;):The plasma concentration time equation of the metabolite may read:where Ctm is plasma concentration of the metabolite of a drug at time t, following the administration of the parent drug at time t = 0; A and B are constants; k., is rate constant of metabolism (acetylation or glucuronidation); and k., is rate constant of elimination. (This may consist of the rate constant of metabolism [k m] and the renal excretion [k r ] . )If the elimination rate of the metabolite is faster than the rate of formation, then the term of the elimination diminishes faster than the term of the formation. Consequently, the rate of formation becomes the rate-limiting factor. This statement is valid in all situations in which one particular metabolic reaction, parent drug-metabolite, is considered, independently of many parallel pathways of elimination. Thus, when the intrinsic elimination of the metabolite is faster than that of the parent compound, the plasma concentration time curves of both compounds must run parallel. 1 This behavior is seen with sulfonamide drugs and their Nr-acetylsulfonamide metabolites as well as with many other compounds undergoing glucuronidation.To determine the intrinsic rate of elimination of the TOM B.126 metabolite, this compound must be administered as a parent compound, preferably by intravenous administration.? For example, it has been shown that N 4 -acetylsulfamethoxazole as a metabolite of sulfamethoxazole elicits a half-life of 9 to 11 hours, similar to that of the parent compound; but as a parent compound it shows a half-life of 3 hours.s-! In general, conjugates exert a higher rate of elimination than their parent compounds.A special situation may exist when the metabolite formed is metabolized back into the parent compound: parent compound~.==========~.metabolite I IThis equilibrium is a result of the metabolic transformation of one or more enzymes. When a one-way reaction is assumed, it appears that the half-life of the metabolite will be similar to that of the parent compound, when the metabolite's intrinsic half-life is much shorter. The question arises whether the plasma concentration time curves of a parent drug and its metabolite still run parallel when both drugs are involved in a metabolic equilibrium, but with a still greater overall elimination rate of the metabolite. Two metabolic reactions that show equilibria are, for example, acetylation" and glucuronidation." For Ni-acetylsulfonamides, two phases (a, f3) in the plasma concentration time curve have been reported. 7 In the case of the benzodiazepine glucuronides, oxazepam glucuronide and 3-hydroxydiazepam glucuronide, it has been reported that the half-life v...

The object of this article is to discuss difficulties in extrapolating the performances of a drug for which the kinetic parameters are derived in healthy volunteers, to patients with severely impaired kidney function. The theoretical background of some actual or probable background is given, and a possible solution for these problems is offered, that is, choosing another drug from the same drug group. In patients without kidney function, metabolism is the only pathway of elimination. When the elimination of the metabolite formed occurs by means of renal excretion only, this metabolite accumulates in patients with impaired or absent kidney function. When a metabolic pathway of the parent drug is part of a metabolic equilibrium, the metabolic return reaction results in an "apparent parent compound," with a half-life identical to that of the accumulated metabolite. In this way, the concentration of the "apparent" parent compound increases and the half-life of the sum of parent and "apparent" parent drug will change. Examples of this drug behavior are given for sulfamethoxazole, sulfametrole, sulfamethizole, procainamide, and N4-acetylprocainamide.