Metabolic Pathway of Drugs - Assignment Example

Name: Professor`s name: Course number: Date: Metabolic Pathways of Drugs The principal site for drug metabolism in the human body is the liver organ. The process of metabolism usually inactivates drugs though some drug metabolites are pharmacologically in active status. Inactive substance which has a metabolite that is active is referred to as a prodrug. Drugs are metabolized by the following processes; reduction, oxidation, conjugation, hydration, hydrolysis, condensation and isomerization. All these processes make the excretion of drugs easier from the body like that of a human being. For metabolism to occur, enzymes must be present. Enzymes are present in body tissues but they are concentrated in the liver. Rates of drug metabolism vary from a patient to another. This is brought about by differences in genetic factors, co-existing disorders and the drug interactions. In many cases of drugs, metabolism occurs in two phases. The phase (I) reactions normally involve the formation of a new functional group. The phase (II) reactions involve the conjugation with a substance that is endogenous such as an acid, sulfate. The reactions in phase (II) are synthetic in nature. Metabolites from synthetic reactions are readily excreted by the kidneys and liver organs. The rate of Metabolism increases with the drug concentration increase. There are two types of metabolism, catabolism and anabolism. In anabolism, energy is directed towards the synthesis of cellular components from small molecules. In catabolism, large molecules are broken down to produce energy. In this paper, I have discussed the metabolism of various drugs, the pathways involved during metabolism and the metabolites of all the discussed drugs as well as the types of metabolism involved. Amphetamines. The first process is the deamination that is followed by oxidation and reduction of the ketone formed. N-oxidation and N-dealkylation follows. Hydroxylation of the aromatic ring and the β-carbon atom takes place. Conjugation with glucuronic acid of the phenol and alcohol products from the ketone formed by deamination finally takes place. 4-Hydroxyphenylacetone,P-Hydroxynorephedrine, 4-Hydroxyamphetamine are the metabolites of Amphetamines. Figure: Structure of D-amphetamine Barbiturates. The oxidation and complete removal of substituents at carbon number five is followed by N-dealkylation of at N1 and N3. Desulfuration at carbon number two is the end process. Thiobarbiturates Scission of the barbiturate ring at the 1:6 bonds occurs to give substituted malonylureas. Barbiturates metabolites are butabarbital, pentobarbital, secobarbital, amobarbital, butalbital, Phenobarbital. Figure: Structure of Barbiturates. Phenothiazines. N-dealkylation in the N10 side chain occurs being followed by N-oxidation in the N10 side chain. Oxidation of the heterocyclic S atom to sulfoxide or sulfone takes place. Hydroxylation of one or both aromatic rings follows and finally Conjugation of phenolic metabolites with glucuronic acid or sulfate Scission of the N10 side chain takes place. Figure: Structure of Phenothiazines. Sulfonamides. Activation at the N4 amino group is the first process. Conjugation with glucuronic acid and sulfate at the N4 amino group follows. Acetylation or conjugation with glucuronic acid at the N1 amino group becomes third process with the hydroxylation and conjugation in the heterocyclic ring, R being the last process. Figure: Structure of sulfonamide Phenytoin. The onset process is the hydroxylation of one aromatic ring, Conjugation of phenolic products with glucuronic acid or sulfate is the subsequent process. Hydrolytic scission of the hydantoin ring, at the bond between carbons number three and four to give 5, 5-diphenylhydantoic acid. 3, 4-dihydroxyphenyl-phenylhydantoin and 3-O-methylated catechol are the metabolites. Figure: Structure of Phenytoin. Moporidine. Onset process is the hydrolysis of ester to acid being followed by N-dealkylation that is followed by hydroxylation of aromatic ring and N-oxidation. N-dealkylation and hydrolysis follow with the last process being the Conjugation of phenolic products formed. The active metabolite of this drug is called norMeperidine. Figure: Structure of alpha-moporidine. Cocaine. Hydrolysis of methyl ester and of benzoate ester is the first and second processes respectively. N-dealkylation, hydrolysis and N-dealkylation follow in that manner. Metabolite of this drug is Benzoylecgonine. Figure: Structure of Cocaine. Phenmetrazine. Oxidation of the drug to lactam forms the first process. Aromatic hydroxylation is followed by N-oxidation and the last process is the conjugation of phenolic products. Phenmetrazine is the active metabolite of phendimetrazine. Figure: Structure of Phenmetrazine. Propranolol. Aromatic hydroxylation at C- 4l is followed by the N-dealkylation. Oxidative deamination is seconded by the oxidation of deaminated product to naphthoxylactic acid. Finally, conjugation with glucuronic acid takes place with O-dealkylation as the last process of propranolol metabolism. The biologically active metabolite is the 4-hydroxypropranolol. Figure: Structure of Propranolol. Diazepam. The N-dealkylation at N1 is followed by hydroxylation at carbon number three (3). Conjugation of phenolic products with glucuronic acid takes place. The N-dealkylation of N1 is followed by hydroxylation at carbon number three (3). Oxazepam is the metabolite of Diazepam. Figure: Structure of Diazepam. Prostaglandins. Reduction of double bonds at carbons numbers 5 and 6, and 13 and 14. Oxidation of 15-hydroxyl to ketone takes place. β-oxidation of carbons 1, 2, 3 and 4 is seconded by ω-oxidation of carbon number (20) to acid. 13, 14-dihydro-15-keto is the metabolite of this drug. Figure: Structure of Prostaglandins. Methadone. Reduction of ketone to hydroxyl is the first process. Aromatic hydroxylation of one aromatic ring is the number two process. N-dealkylation of alcohol product and N-dealkylation with cyclization to pyrrolidine are the last processes. 2-ethylidene-1, 5-dimethyl-3, 3-diphenylpyrrolidine are the major metabolites, Figure: Methadone structure. Piroxicam. Pyridine 3l-hydroxylation is the onset process with hydrolysis of amide being second and finally process being decaboxylation. 5`-hydroxypiroxicam is the major metabolite. Figure: structure of Piroxicam. Caffeine. N3-demethylation is followed by N1-demethylation. Third process is the N7-demethylation to theophylline. C-8 oxidation to uric acids is the fourth process that leads to Imidazole ring being opened. Metabolites are 5-acetylamino-6-formylamino-3-methyluracil, 1-methyluric acid, 1-methylxanthine and 1, 7-dimethyluric acid. Figure: Structure of Caffeine. Tamoxifen. N-demethylation is the onset process that is followed by the 4l- hydroxylation which in turn is followed by the N-oxidation (FMO). 4-O-sulfation take place and 4-O-glucuronide is the final process of the metabolism. 4-hydroxy, 4'-hydroxy and N-desmethyl are major metabolites. Figure: Structure of Tamoxifen. Tripelennamine. The first process that takes place is the p-hydroxylation. Benzylic C-hydroxylation is the next pathway with N-debenzylation as the final pathway. The N`,N`-Dimethyl-N- (2-Pridyl)-1, and 2-ethanediamine are the metabolites. Figure: Structure of Tripelennamine. Felodipine. The first process involves the Aromatization of the drug. The subsequent process involves the hydrolysis of the esters and the final process is the methyl hydroxylation. 1-[(2,4-dichlorophenyl)carbamoyl]ethyl 4,6-dimethyl-2-oxo-2H-pyran-5-carboxylate is metabolite of felodipine. Figure: Structure of Felodipine. References Anzenbacher, Pavel, and Ulrich M. Zanger. Metabolism of Drugs and Other Xenobiotics. Hoboken, N.J: Wiley-VCH, 2012. Internet resource. Read More