China
Africa
Explore chapters and articles related to this topic
Substrates of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Procainamide is a class Ia antiarrhythmic agent used for the treatment of both supraventricular and ventricular arrhythmias (Winkle et al. 1975). It differs from procaine, which is the p-aminobenzoyl ester of 2-(diethylamino)-ethanol. Procainamide has a similar effect to quinidine. A substantial but variable fraction of procainamide is metabolized by cytosolic N-acetyltransferase 2 (NAT2) to N-acetylprocainamide (Figure 3.58), ranging from 16% to 21% of an administered dose in slow acetylators and from 24% to 33% in fast acetylators (Budinsky et al. 1987; Coyle et al. 1985; du Souich and Erill 1977; Karlsson 1978). Patients treated with procainamide have plasma concentrations of N-acetylprocainamide generally equaling or being two to three times greater than those of the parent drug (Atkinson et al. 1988). N-Acetylprocainamide (acecainide) appears less potent than procainamide with regard to antiarrhythmic effect, and it is used as a class III antiarrhythmic agent (Bagwell et al. 1976; Dangman and Hoffman 1981; Harron and Brogden 1990). Procainamide also undergoes N-deethylation to form a desethyl derivative that can be further acetylated (Ruo et al. 1981). Trace amounts may be excreted in the urine as free and acetyl-conjugated p-aminobenzoic acid, which is formed by direct hydrolysis, 30% to 60% as unchanged procainamide and 6% to 52% as the N-acetylprocainamide derivative (Karlsson 1978). Both procainamide and N-acetylprocainamide are eliminated by active tubular secretion as well as by glomerular filtration. Procainamide is converted by CYP2D6 to reactive N-hydroxyprocainamide (Figure 3.58) (Lessard et al. 1997), which may be responsible for lupus erythematosus and skin rashes observed in patients treated with the drug (Katsutani and Shionoya 1992). Sequential oxidations at the arylamine moiety of procainamide by hepatic CYP2D6 and myeloperoxidase (MPO) in activated leukocytes result in nitrosoprocainamide, which can be conjugated with glutathione (GSH) by glutathione S-transferase (GST) to form a stable conjugate via an initial unstable mercaptal derivative (Freeman et al. 1981; Uetrecht 1985; Wheeler et al. 1991). The incidence of procainamide-induced lupus erythematosus has been reported to be as high as 30% of patients receiving prolonged procainamide therapy (Lawson and Jick 1977). Procainamide-induced lupus erythematosus is characterized by the production of antibodies against nuclear histones and, in particular, to the histone H2A/H2B dimer (Burlingame 1997; Burlingame and Rubin 1996; Katsutani and Shionoya 1992; Mongey and Hess 2001). Rapid acetylators required longer time to develop lupus erythematosus than slow acetylators (Woosley et al. 1978).
N-acetyltransferase: the practical consequences of polymorphic activity in man
Published in Xenobiotica, 2020
The polymorphic acetylation of this drug has been demonstrated in both patients and healthy individuals (Gibson et al., 1975; Karlsson & Molin, 1975; Ylitalo et al., 1983). About a quarter of the dose is metabolised by N-acetylation to produce the less toxic, N-acetylprocainamide, which itself has been employed as the antiarrhythmic compound, acecainide. Its elimination half-life may be markedly prolonged in patients who are slow acetylators (Parmley, 1983). Its usage is marred by many adverse reactions (Lawson & Jick, 1977) with lupus-like signs being reported in up to 40% of those receiving chronic oral therapy (Parmley, 1983). Other workers have indicated a lower incidence (10–20%) for the lupus problems but state that most patients taking procainamide develop antinuclear antibodies (Mongey et al., 1999; Tan & Rubin, 1984). The length of exposure and the dose appear related to the development of such antibodies and suggest that it is the parent compound, and not the metabolite, that is the causative agent. However, non-acetylated metabolites may also play a part (Woosley et al., 1978; Ylitalo et al., 1983). Interestingly, acecainide (N-acetylated procainamide) has a similar degree of side-effects to procainamide except for the lupus-like syndrome (Atkinson et al., 1983; Roden et al., 1980). This suggests that prolonged exposure to the parent drug may aggravate the precipitation of lupus problems and hence slow acetylators may be more at risk. As a consequence, the usage of procainamide is limited.