Procainamide Aminobenzoic acid

Although the two forms of the enzyme have preferred substrates, there is overlap between them such that no substrate seems to be exclusively acetylated by one or the other. Some preferred NAT1 substrates are p-aminobenzoic acid and p-aminosalicylic acid and sulfanilamide, whereas preferred substrates for NAT2 include isoniazid, hydralazine, procainamide, and dapsone. 

Figure 5.23 Frequency distribution for the acetylation of (A) procainamide (B) and p-aminobenzoic acid in human subjects. Data represents excretion of acetylated product in the urine 6 hours after dosing. Source From Ref. 28.

Abbreviations-. PA BA, p-aminobenzoic acid PAS, p-aminosalicylic acid PA, procainamide SMZ, sulfamethazine. 

It should be noted that in the hamster the situation is the reverse, with p-aminobenzoic acid and p-aminosalicylic acid being polymorphically acetylated and sulfamethazine and procainamide monomorphically acetylated. 

FIGURE 5.IS Metabolism of procainamide. Procainamide and the hydrolysis productp-aminobenzoic acid are both acetylated. 

PABA, /7-aminobenzoic acid PAS, / -aminosalicylic acid PA, procainamide SMZ, sulphamethazine. Data from Weber (1987) The Acetylator Genes and Drug Response (New York Oxford University Press). 

A single case report found that para-aminobenzoic acid (PABA) increased the serum levels of procainamide and reduced the serum levels of the procainamide metabolite N-acetylprocainamide. In contrast, a later pharmacokinetic study in healthy subjects found that PABA had no effect on serum procainamide levels, and increased serum IV-acetylprocainamide levels. 

A 61-year-old man who had sustained ventrieular tachycardia, which did not respond adequately to oral procainamide, was found to be a fast acetylator of procainamide, which resulted in particularly high serum levels of the procainamide metabolite (7V-acetylprocainamide) when compared with the procainamide levels. When he was also given para-aminobenzoic acid (PABA) 1.5 g every 6 hours for 30 hours, to suppress the production of this metabolite, the serum level of procainamide increased, that of Al-acetylproeainamide decreased, and control of his arrhythmia improved. However, a later study in 10 healthy subjects, who were also fast acety lators, found that PABA did not significantly affect the pharmacokinetics of procainamide. In addition, although PABA inhibited the production of A-acetylprocainamide, it also inhibited renal excretion, so that the AUC and elimination half-life were increased. This suggests that PABA may in fact not be useful for increasing the efficacy and safety of procainamide. ... 

Nylen ES, Cohen AI, Wish MH, Lima JL, Finkelstein JD. Reduced acetylation of procainamide by para-aminobenzoic acid. J Am Coll Card ol 0 986) 7,185-7. 

Tisdale JE.Rudis MI, Padhi ID, SvenssonCK, WebbCR, Borzak S, Ware JA,KrepostmanA, Zarowitz BJ, Inhibition of N-acetylation of procainamide by para-aminobenzoic acid in humans. J Clin Pharmacol (1995) 35, 902-10. 

The activation of ester prodmgs via the action of esterases is described above and in various other chapters, e.g. Chapter 5 and Chapter 22. Esterases are also employed to inactivate dmgs or to prepare them for phase II conjugation. For example, the local anaesthetic lidocaine is rapidly hydrolysed to p-aminobenzoic acid deactivating it (Fig. 8.35). The closely related antianythmic compound procainamide is not readily hydrolysed and its major deactivated metah-olite is desethyl procainamide (Fig. 8.35), although much of the dmg is excreted unchanged. Hydrolysis of esters occurs much more readily than the hydrolysis of amides... 

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