Quinidine biotransformation

The answer is b. (Hardman, p 906.) Cimetidine reversibly inhibits cytochrome P450. This is important in phase I biotransformation reactions and inhibits the metabolism of such drugs as warfarin, phenytoin, propranolol, metoprolol, quinidine, and theophylline. None of the other enzymes are significantly affected. 

Donepezil, rivastigmine, and galantamine are newer cholinesterase inhibitors with adequate penetration into the CNS and a spectrum of action more limited to indirect cholinomimetic effects than tacrine s. The cholinesterase inhibitors should be used with caution in patients receiving other drugs that inhibit cytochrome P450 enzymes (eg, ketoconazole, quinidine see Chapter 4 Drug Biotransformation). 

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. 

However, quinidine is not biotransformed by CYP2D6, even though it binds to this enzyme with high affinity [unbound A) < 1 nM (34)]. Quinidine is actually biotransformed by CYP3A4 (35), and is a competitive inhibitor of this enzyme [A) as low as 5.4 pM (36)], although its effects are highly dependent on the CYP3A4 substrate employed. 

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). 

Quinidine is primarily eliminated by biotransformation in the liver. About 80% of a dose is metabolized to active metabolites of varying activity. The contribution of these metabolites to efficacy/toxicity is not fully known. ... 

CYP2D6 is involved in the biotransformation of 15-20% of drugs undergoing oxidative metabolism. Important inhibitors include cimetidine, fluoxetine, paroxetine, amiodarone, quinidine and ritonavir. 

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