China
Africa
Explore chapters and articles related to this topic
Biomedical Accelerator Mass Spectrometry
Published in Graham Lappin, Simon Temple, Radiotracers in Drug Development, 2006
In the 1970s, a method of determining absolute bioavailability using a stable isotope was developed.30 An intravenous dose of N-acetylprocainamide, labeled with 13C, was administered simultaneously with an unlabeled oral dose. There was therefore a single-dose occasion and a single set of plasma samples taken. By analyzing the plasma samples, it was possible to deconvolute the concentrations of the intravenous dose from the oral dose. Essentially, the method relies on isotopic dilution (Section 4.5). The intravenous and oral doses mix as they enter the bloodstream. The proportion of the oral dose that reaches the bloodstream is thus proportional to the degree of isotopic dilution of the intravenous dose. The plasma concentrations for the two doses were separated by virtue of the different molecular weights, using mass spectroscopy. Since it was possible to determine the concentrations of both the intravenous dose and the oral dose from the same plasma samples, any issues of dose dependency were eliminated, irrespective of the initial doses administered.
Antidysrhythmic Drugs in Pediatrics
Published in Sam Kacew, Drug Toxicity and Metabolism in Pediatrics, 1990
Howard C. Mofenson, Thomas R. Caraccio, Kathleen Mimnagh, Peter Bruzzo
Approximately 75 to 95% of procainamide is absorbed following oral administration and 15% of the drug undergoes first-pass hepatic elimination.62,63 In the liver, procainamide is metabolized to N-acetylprocainamide by the enzyme N-acetyl transferase. The activity of the enzyme is polymodally distributed, with half of the patients being slow acetylators and half being fast acetylators, eliminating 12 and 23% of orally administered procainamide dose as NAPA, respectively.4,64 Only 15% of the drug is protein-bound.3,4 In children the drug is rapidly distributed (approximately 10 min) and rapidly cleared with an elimination half-life of 1.7 h.65 In adults, however, procainamide is eliminated more slowly, with an elimination half-life of 2.2 to 4.7 h.62,63,66 In children as in adults, the elimination of procainamide can be significantly altered in renal insufficiency, since as much as 50% of the administered dose of procainamide appears unchanged in the urine.68 Gibson et al.68 found a 11- to 16-h increase in the elimination half-life of procainamide in adult patients with renal failure. Proper dosing of procainamide can be difficult in patients with renal failure also because elevated plasma procainamide levels can lead to markedly elevated plasma levels of NAPA, which has a half-life of elimination twice that of procainamide (6 to 8 h vs. 3 to 4 h).59 In renal disease, it may be impossible to achieve therapeutic procainamide levels without concomitant toxic elevation of the plasma NAPA levels.4a,b
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.