Quinidine metabolite

High Pressure Liquid Chromatography. In plasma quinidine and other anti-arrhythmic agents, sensitivity 500 ng/ml, UV detection—R. R. Bridges and T. A. Jennison, J. analyt. Toxicol., 1983, 7, 65-68. In plasma quinidine, hydroquinidine, and 2 quinidine metabolites, sensitivity 50 ng/ml for quinidine, fluorescence detection—L. K. Pershing eta/., J. analyt. Toxicol., 1982, 6,153-156. In plasma or urine quinidine, hydroquinidine and quinidine metabolites, detection limit 10 ng/ml for quinidine, fluorescence and UV detection—T. W. Guentert et al., J. Chromat., 1980,183, Biomed. AppL, 9, 514-518. 

Felodipine 10 mg daily for 3 days was found to have no clinically significant effect on the pharmacokinetics or haemodynamic and ECG effects of a single 400-mg dose of quinidine in 12 healthy subjects. Felodipine did cause a modest 22% decrease in the AUC of the quinidine metabolite 3-hydroxyquinidine. ... 

Rifampicin is a potent enzyme-inducer, which markedly increases the metabolism of the quinidine by 3-hydroxylation and N-oxidation, thereby reducing its levels and effects. It has been suggested that two of the quinidine metabolites (3-hydroxyquinidine and 2-oxoquinidinone) may be active, which might, to some extent, offset the effects of this interaction. 

Metabolism/Excretion - From 60% to 80% of a dose is metabolized via the liver into several metabolites. Quinidine is excreted unchanged (10% to 50%) in the urine within 24 hours. The elimination half-life ranges from 4 to 10 hours in healthy patients, with a mean of 6 to 7 hours. Urinary acidification facilitates quinidine elimination, and alkalinization retards it. In patients with cirrhosis, the elimination half-life may be prolonged and the volume of distribution increased. 

Drugs that might be affected by lopinavir/ritonavir include ergot derivatives, oral contraceptives, antiarrhythmics, HMG-CoA reductase inhibitors, HIV protease inhibitors, atovaquone, calcium channel blockers, ketoconazole, itraconazole, pimozide, cisapride, clarithromycin, disulfiram, metronidazole, immunosuppressants, midazolam, triazolam, narcotic analgesics, rifabutin and rifabutin metabolite, sildenafil, warfarin, bupropion, clozapine, desipramine, piroxicam, quinidine, theophylline, and zolpidem. 

Quercetin has been found to inhibit P-gp-mediated efflux of ritonavir in Caco-2 cells (47), to reduce the oxidation of acetaminophen in rat liver microsomes and HepG2 cells (48), and to inhibit the metabolism of midazolam and quinidine in human liver microsomes (49). It did not have an effect on CYP3A4-mediated metabolism and P-gp-mediated transport of saquinavir (41). Rutin was demonstrated to moderately increase the uptake of idar-ubicin in an isolated perfused rat lung model, and also the outflow recovery of the major metabolite idarubicinol, possibly by affecting P-gp (45). Nobe-litin and tangeretin were shown to inhibit OATP-B-mediated uptake of estrone-3-sulfate into human embryonic kidney cells (23). 

Quinidine is 70-80% bioavailable following oral administration. It is 80% bound to albumin and a i-acid glycoprotein. It is eliminated primarily by hepatic metabolism. The principal metabolite, 3-hydroxy quinidine is biologically active with half the activity of the parent compound. Twenty percent of the quinidine dose appears in the unchanged form in the urine. The elimination half-life is 6-8 hours. Quinidine is usually administered in a slow release formulation, eg, that of the gluconate salt. 

In spite of the investigation of the in vivo mammalian metabolism of other alkaloids of the quinoline type, such as the biotransformations of quinidine in man (182), and the characterization of the metabolites (183, 184), there have been no other reports of microbial or in vitro enzymic transformations of other alkaloids of this group. 

One of the complicating factors with chemical inhibitors is that a chemical that inhibits one CYP enzyme may activate another enzyme. If both enzymes contribute to metabolite formation, the inhibitory effect of the chemical on one enzyme may be offset by its activating effect on the other enzyme. a-Naphthoflavone is an inhibitor of CYP1A2 but an activator of CYP3A4, whereas quinidine is an inhibitor of CYP2D6 but, in certain cases, an activator of CYP3 A4 (184-186). a-Naphthoflavone and quinidine both appear on the list of FDA preferred and acceptable chemical inhibitors, so their ability to inhibit one enzyme but activate another are relevant to reaction phenotyping. 

A second group of workers has concurred168 that one of the major metabolites of quinidine in man22" is the 5 -hydroxy-derivative. 

C19 2D6 Mephenytoin (4-hydroxy metabolite), Omeprazole Bufuralol, Dextromethorphan Metoprolol, Debrisquine, Codeine Tranylcypromine Quinidine Ticlopidine (but also inhibits 2D6), Nootkatone (but also inhibits 2A6)... 

FIGURE 19.3 Predicted changes in QT interval after administration of intravenous (dotted line) and oral (solid line) single doses of quinidine to healthy subjects (12). The delay in effect lAuth respect to plasma concentration causes hysteresis loops. The slope of the biophase concentration effect relationship is greater after oral doses due to active metabolites formed during quinidine absorption. (Reproduced with permission from Holford NHG, Coates PE, Guentert tW, Riegelman S, Sheiner LB. Br J Clin Pharmacol 1981 11 187-95.)... 

A linear model also was used to relate bio phase quinidine concentrations to the time course of electrocardiographic QT interval changes after intravenous and oral dosing of this drug (12). As shown in Figure 19.3/ the slope was greater after oral doses and that was attributed to the formation of active metabolites of quinidine during first-pass metabolism of the oral dose (13). 

Holford NHG, Coates PE, Guentert TW, Riegelman S, Sheiner LB. The effect of quinidine and its metabolites on the electrocardiogram and systolic time intervals Concentration-effect relationships. Br J Clin Pharmacol 1981 11 187-95. 

Pharmacokinetics. Absorption of quinidine from the gut is rapid, 75% of the drug is metabolised and the remainder is eliminated unchanged in the urine (t/ 7 h). Active metabolites may accumulate when renal function is impaired. 

C. Funck-Brentano, H. K. Kroemer, H. Pavlou, R. L. Woosley and D. M. Roden, "Genetically-determined interaction between propafenone and low dose quinidine Role of active metabolites in modulating net drug effect," Br. /. Cii . Pharmacol., 27 435-444 (1989). 

The antiarrhythmic agent quinidine is metabolized by allylic hydroxylation to 3-hydroxyquinidinc. the principal plasma metabolite found in humans. This metabolite shows significant antiarrhythmic activity in animals and po.s-sibly in humans. -"... 

Perhaps the only contribution of much chemical interest in the Cinchona group during the year concerns the biotransformation of quinidine (234) in man, and the partial synthesis of one of the metabolites. The two metabolites identified were 3-hydroxyquinidine (235) and 2 -quinidinone, the 2-quinolone analogue of quinidine the former of these was prepared from quinidine by degradation to the ketone (236) (not previously prepared), and re-introduction of the vinyl group by a Grignard synthesis (Scheme 32). 

Bonora et al 3,43 described a method for the analysis of quinidine in urine Rakhit et al.33 and Patel74 reported methods suited for the analysis of quinidine in urine. LagerstrBm31 injected urine directly on the column for the analysis of quinidine. Barrow et al.47 reported the analysis of quinine and quinidine and their respective metabolites in rat urine. Flood et al.43 determined simultaneously three antiarrhytmic drugs in plasma by means of HPLC. As a common dilutant for drugs of abuse, quinine is often found and determined in mixtures of such drugs (Table 5.1). The analysis of quinine in soft drinks have also been accomplished by means of HPLC (Table 5.6). 

Most of the mobile phases employed in the analysis of quinidine in biological fluids are acidic. Drayer et al. 1 6 and Leroyer et al. 7 separated quinidine and its metabolites by using acetonitrile-acetic acid-water in combination with an octadecyl column (Fig. 5.2). Barrow et al.47 used a similar system, but preferred a gradient elution to separate quinine and quinidine from their respective metabolites. Acidic buffers have... 

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