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//-->1Review of Drug Metabolism in DrugDiscovery and DevelopmentRONALD E. WHITEWhite Global Pharma Consultants, LLC, Cranbury, NJ, USA1.11.21.31.41.51.61.71.8SummaryIntroductionThe phenomenon of drug metabolismThe drug discovery and development processThe significance and importance of drug metabolismThe biochemical process of drug metabolismThe chemical characterization of drug metabolismConclusionAbbreviationsReferences123121419303334341.1SUMMARYDrug metabolism is a physiological phenomenon in which xenobiotic compoundsare chemically transformed into metabolites of the parent drug. Drug metabolismcomprises a diverse set of chemical reactions within four general categories: oxidation,reduction, conjugation, and hydrolysis. These general categories of chemical reactionscorrespond to general categories of enzymes, which are responsible for catalyzing thereactions. The object of drug metabolism is to clear the xenobiotics from the body, sothat the metabolites tend to be more polar and soluble than the parent drug, makingthem easier to excrete. Transporters are now recognized as a necessary component ofdrug metabolism, since they facilitate penetration of the parent drug into metabolizingorgans and passage of ionic metabolites across cell membranes into the excreta. Drugmetabolism is important in the clinical action of drugs because it is often the mainmeans by which drugs are cleared from the body, so the rate of metabolism is one deter-minant of the elimination half-life of the drug. Drug metabolism is additionally impor-tant because the metabolites may have pharmacological or toxicological properties,which are superimposed on the clinical profile of the parent drug. For these reasons, thedrug discovery process aims to design molecules with rates of metabolism appropriatefor clinical use and pathways of metabolism which minimize side effects or toxicitiesattributable to metabolites. In clinical development, characterization of the metabolicEncyclopedia of Drug Metabolism and Interactions, 6-Volume Set,First Edition.Edited by Alexander V. Lyubimov.©2012 John Wiley & Sons, Inc. Published 2012 by John Wiley & Sons, Inc.12REVIEW OF DRUG METABOLISM IN DRUG DISCOVERY AND DEVELOPMENTpathways, the major circulating metabolites, and the enzymes that produce thesemetabolites is necessary for a full understanding of the clinical profile of a new drug.Accordingly, several types of clinical studies of metabolism are mandated for new drugregistration, including identification and quantitation of major circulating metabolites,determination of the major pathways of clearance (CL) and their associated metabolicenzymes, characterization of drug–drug interactions based on metabolic phenomena,and assessment of the extent of excretion of drug-derived materials from the body.1.2INTRODUCTIONWhen an organic compound enters the human body, it is normally (i) utilized as anutrient, (ii) directly excreted, or (iii) chemically modified and then excreted. In thecase of a nutrient, the molecules enter specific biochemical pathways that either splitthem into small units followed by complete oxidation to generate energy (catabolism)or utilize them as precursors for constructing physiological molecules such as nucleicacids, polysaccharides, proteins, and triglycerides (anabolism). The overall process ofutilization of nutrients is calledintermediary metabolism.An example is the splittingof dietary fatty acids such as palmitic acid into two-carbon acetyl CoA units that canbe oxidized in the mitochondria to produce energy (as ATP).CH3−(CH2)14−COOH →8CH3CO−SCoA→16CO2+12H2O(+107ATP)In cases of nonnutrient compounds (xenobiotics), however, pathways for signif-icant energy production seldom exist, although in some cases the body is able topartially metabolize an organic compound for its energy content, as for instance withN-demethylation of drugs (Section 1.3).R−NMe2+NADPH+O2→R−NHMe+HCHO→HCOOH+NADH→CO2+NADH(equivalentto 3ATPs)The methyl group is released as formaldehyde, which is further oxidized to for-mate and finally carbon dioxide, generating 2 mol of NADH. However, since 1 molof NADPH must be invested for the metabolic demethylation, then the net energyproduction is 1 mol of NADH, equivalent to 3 mols of ATP. Most such reactions ofxenobiotics are either energy-neutral (e.g., hydrolyses) or actually energy-consumptive(e.g., hydroxylations), since they produce no energy equivalents, but may use cofactorssuch as NADPH, PAPS, SAM (S-adenosine-L-methionine), or UDPGA, which requirecellular ATP equivalents for their synthesis.With the majority of xenobiotics, only a limited set of nonspecific chemical modi-fications is possible. This process is calleddrug metabolism,although it occurs withall absorbed foreign compounds, and not just drugs. To avoid confusion with interme-diary metabolism, drug metabolism is sometimes calledbiotransformation.However,in fact, there is rarely any serious confusion between these two terms, and the termbiotransformationis not really descriptive enough to convey a clear meaning in anyevent. So, most scientists working in this field simply call itdrug metabolism.Forthe purposes of this chapter, we make no distinction between xenobiotic chemicalTHE PHENOMENON OF DRUG METABOLISM3compounds that are unintentionally introduced into the body (e.g., natural plant alka-loids or environmental chemicals) and those that are intentionally dosed (e.g., medicinaldrugs). The same CL mechanisms operate on all xenobiotics, and we use the termdrugmetabolismto describe the chemical modification of any nonphysiological compound.Drug metabolism occurs in all species, from bacteria to humans, but our primary focusin this chapter is the human phenomenon, only with reference to other species, as theyare relevant to the process of discovery and development of new drugs. An increas-ing proportion of new drugs are proteins and nucleic acids (i.e.,biologics),but thescope of this chapter is limited to the discussion of traditional small-molecule organiccompounds.The recognition that foreign substances may be metabolized in the body goes backalmost two centuries, and an interesting history of the early discoveries is availablein the form of a journal article [1] or website [2]. About 60 years ago, biochemistsbegan to recognize drug metabolism as a distinct field of study. Soon, scientists inacademia, pharmaceutical companies, and regulatory agencies realized that character-ization of the metabolic fate of drugs was an important component in understandingtheir clinical profiles. Initially, it was sufficient to merely demonstrate that a doseddrug and/or its metabolites were eliminated from the body in a reasonable amount oftime. Next, in the evolution of drug metabolism, there was a need to determine thechemical form of the major drug-related materials in the excreta. Today, the potentialrole of circulating metabolites in therapeutic action as well as toxicity has becomeapparent, and a sophisticated quantitative chemical, biochemical, pharmacological,and toxicological description of metabolism is required for the registration of newdrugs.Finally, we can ask “What is the object of drug metabolism?” As can be seen insubsequent sections, drug metabolism is more than just an attempt by the body to “eat”ingested foreign compounds. The existence of a complex, regulated, and interacting setof barriers and CL mechanisms suggests that the object is to chemically and physicallylimit the entry of these compounds to the body and facilitate their removal from thebody. Those compounds that are not clearable by direct excretion in urine or feces aresubject to sequential rounds of metabolism, which change their chemical and physicalproperties until theycanbe excreted. With these thoughts in mind, let us discuss indetail exactly what drug metabolism is and why it is important to the discovery anddevelopment of new drugs.1.3THE PHENOMENON OF DRUG METABOLISMDrug metabolism comprises such a rich variety of chemical modifications of organiccompounds that it is rare to find a drug that is not subject to some type of metabolicprocess. Of course, there is a kinetic component of the drug-metabolism process aswell, so in some cases the metabolism occurs only slowly. For example, amiodaroneis cleared from the body exclusively by metabolism [3], but because the metabolicprocess is very slow, this drug has a 55-day terminal half-life [4]. In other cases, thedirect excretion process is much faster than metabolism and dominates CL. So we findthat amoxicillin, for example, is mainly excreted as the intact parent drug in urine [5].Nonetheless, most drugs are rapidly metabolized as the major route of CL from thebody. Although the diverse manifold of possible reactions presents a complex array of4REVIEW OF DRUG METABOLISM IN DRUG DISCOVERY AND DEVELOPMENTpossibilities, we can recognize some patterns, so that it is possible to use relatively fewterms to describe virtually all the transformations. In fact, there are only four majorcategories: oxidations, reductions, conjugations, and hydrolyses.These four categories of chemical transformation arise from four broad classesof enzymes, which actually accomplish the transformation for a particular drug. It iscommon, if not universal, for a particular drug to be subject to more than one metabolicconversion. For example, dextromethorphan has two major metabolites, one resultingfrom N-demethylation and the other from O-demethylation (Fig. 1.1).As one would expect, some metabolites are the product of sequential operation oftwo or more of these basic transformations, as shown for loratadine, which under-goes oxidative decarboethoxylation followed by aromatic hydroxylation and finallyglucuronidation (Fig. 1.2).Occasionally, a metabolic pathway apparently not conforming to this fourfold cat-egorization is encountered, as shown in Fig. 1.3.However, almost always, closer examination shows that the process was actually adiversion during operation of one of the four standard categories [8,9]. In the examplein Fig. 1.3, pulegone is first hydroxylated on an allylic methyl group, followed byinternal hemiketal formation and dehydrative aromatization to form menthofuran [10].H3COH3CO+HONCH3NHNCH3Figure 1.1N- and O-demethylation of dextromethorphan [6].ClNNClNCO2EtNHHOOCHOHOOOHONClHONClNHNHFigure 1.2Metabolic pathway for loratadine [7].THE PHENOMENON OF DRUG METABOLISMOO5Figure 1.3Ring closure of pulegone to menthofuran.H3CONF3CCH3CH3F3CNH3CNNOCH3H3CONCH3CH3NH3COCH3N NOHNNFigure 1.4Ring contraction of vicriviroc [11].A more vexing example is provided below by the contraction of a six-memberedpyrimidine ring to a five-membered pyrazole ring in the anti-HIV drug vicriviroc(Fig. 1.4). Although no explanation for this reaction had been published, one canwrite a plausible, albeit complex, metabolic pathway linking the parent drug and themetabolite utilizing only known reactions from the four standard categories (detailsleft as an exercise for the reader).Although many interesting chemical transformations are known in biochemistry, welimit our discussion here only to ones that have been demonstrated to occur with xeno-biotics. Table 1.1 summarizes the main chemical reactions of human drug metabolism.Each metabolic reaction has been given a name descriptive of the overall chemicaltransformation that occurs, regardless of the internal mechanism by which the trans-formation was accomplished. However, in many cases, the metabolic reaction has aname commonly used in the published literature of drug metabolism. For example,“introduction of an oxygen atom at an aliphatic position” would typically be referredto asHydroxylation,even though an oxygen atom, not a hydroxyl group was addedto the molecule. The common name is given in parenthesis. Note that the drugs andmetabolites are drawn in their unionized forms to better see the chemical transforma-tion that has occurred. Although Table 1.1 is intended to be reasonably comprehensivefor introductory purposes, it is not exhaustive. A number of unusual examples havebeen compiled elsewhere [8,9].Finally, it is worth noting that some metabolic reactions can be reversed, leadingto the phenomenon offutile cycling.A metabolite that is produced through one of themetabolic reactions in Table 1.1 may be reconverted to the parent drug by anothermetabolic reaction, with no net chemical transformation. An example is the conver-sion of a tertiary amine to anN-oxide(Reaction I.F). Since someN-oxidescan bereduced to tertiary amines (Reaction II.B), the result is that the amine appears not tohave been metabolized, when in fact two metabolic steps occurred [32]. The existence [ Pobierz całość w formacie PDF ]
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//-->1Review of Drug Metabolism in DrugDiscovery and DevelopmentRONALD E. WHITEWhite Global Pharma Consultants, LLC, Cranbury, NJ, USA1.11.21.31.41.51.61.71.8SummaryIntroductionThe phenomenon of drug metabolismThe drug discovery and development processThe significance and importance of drug metabolismThe biochemical process of drug metabolismThe chemical characterization of drug metabolismConclusionAbbreviationsReferences123121419303334341.1SUMMARYDrug metabolism is a physiological phenomenon in which xenobiotic compoundsare chemically transformed into metabolites of the parent drug. Drug metabolismcomprises a diverse set of chemical reactions within four general categories: oxidation,reduction, conjugation, and hydrolysis. These general categories of chemical reactionscorrespond to general categories of enzymes, which are responsible for catalyzing thereactions. The object of drug metabolism is to clear the xenobiotics from the body, sothat the metabolites tend to be more polar and soluble than the parent drug, makingthem easier to excrete. Transporters are now recognized as a necessary component ofdrug metabolism, since they facilitate penetration of the parent drug into metabolizingorgans and passage of ionic metabolites across cell membranes into the excreta. Drugmetabolism is important in the clinical action of drugs because it is often the mainmeans by which drugs are cleared from the body, so the rate of metabolism is one deter-minant of the elimination half-life of the drug. Drug metabolism is additionally impor-tant because the metabolites may have pharmacological or toxicological properties,which are superimposed on the clinical profile of the parent drug. For these reasons, thedrug discovery process aims to design molecules with rates of metabolism appropriatefor clinical use and pathways of metabolism which minimize side effects or toxicitiesattributable to metabolites. In clinical development, characterization of the metabolicEncyclopedia of Drug Metabolism and Interactions, 6-Volume Set,First Edition.Edited by Alexander V. Lyubimov.©2012 John Wiley & Sons, Inc. Published 2012 by John Wiley & Sons, Inc.12REVIEW OF DRUG METABOLISM IN DRUG DISCOVERY AND DEVELOPMENTpathways, the major circulating metabolites, and the enzymes that produce thesemetabolites is necessary for a full understanding of the clinical profile of a new drug.Accordingly, several types of clinical studies of metabolism are mandated for new drugregistration, including identification and quantitation of major circulating metabolites,determination of the major pathways of clearance (CL) and their associated metabolicenzymes, characterization of drug–drug interactions based on metabolic phenomena,and assessment of the extent of excretion of drug-derived materials from the body.1.2INTRODUCTIONWhen an organic compound enters the human body, it is normally (i) utilized as anutrient, (ii) directly excreted, or (iii) chemically modified and then excreted. In thecase of a nutrient, the molecules enter specific biochemical pathways that either splitthem into small units followed by complete oxidation to generate energy (catabolism)or utilize them as precursors for constructing physiological molecules such as nucleicacids, polysaccharides, proteins, and triglycerides (anabolism). The overall process ofutilization of nutrients is calledintermediary metabolism.An example is the splittingof dietary fatty acids such as palmitic acid into two-carbon acetyl CoA units that canbe oxidized in the mitochondria to produce energy (as ATP).CH3−(CH2)14−COOH →8CH3CO−SCoA→16CO2+12H2O(+107ATP)In cases of nonnutrient compounds (xenobiotics), however, pathways for signif-icant energy production seldom exist, although in some cases the body is able topartially metabolize an organic compound for its energy content, as for instance withN-demethylation of drugs (Section 1.3).R−NMe2+NADPH+O2→R−NHMe+HCHO→HCOOH+NADH→CO2+NADH(equivalentto 3ATPs)The methyl group is released as formaldehyde, which is further oxidized to for-mate and finally carbon dioxide, generating 2 mol of NADH. However, since 1 molof NADPH must be invested for the metabolic demethylation, then the net energyproduction is 1 mol of NADH, equivalent to 3 mols of ATP. Most such reactions ofxenobiotics are either energy-neutral (e.g., hydrolyses) or actually energy-consumptive(e.g., hydroxylations), since they produce no energy equivalents, but may use cofactorssuch as NADPH, PAPS, SAM (S-adenosine-L-methionine), or UDPGA, which requirecellular ATP equivalents for their synthesis.With the majority of xenobiotics, only a limited set of nonspecific chemical modi-fications is possible. This process is calleddrug metabolism,although it occurs withall absorbed foreign compounds, and not just drugs. To avoid confusion with interme-diary metabolism, drug metabolism is sometimes calledbiotransformation.However,in fact, there is rarely any serious confusion between these two terms, and the termbiotransformationis not really descriptive enough to convey a clear meaning in anyevent. So, most scientists working in this field simply call itdrug metabolism.Forthe purposes of this chapter, we make no distinction between xenobiotic chemicalTHE PHENOMENON OF DRUG METABOLISM3compounds that are unintentionally introduced into the body (e.g., natural plant alka-loids or environmental chemicals) and those that are intentionally dosed (e.g., medicinaldrugs). The same CL mechanisms operate on all xenobiotics, and we use the termdrugmetabolismto describe the chemical modification of any nonphysiological compound.Drug metabolism occurs in all species, from bacteria to humans, but our primary focusin this chapter is the human phenomenon, only with reference to other species, as theyare relevant to the process of discovery and development of new drugs. An increas-ing proportion of new drugs are proteins and nucleic acids (i.e.,biologics),but thescope of this chapter is limited to the discussion of traditional small-molecule organiccompounds.The recognition that foreign substances may be metabolized in the body goes backalmost two centuries, and an interesting history of the early discoveries is availablein the form of a journal article [1] or website [2]. About 60 years ago, biochemistsbegan to recognize drug metabolism as a distinct field of study. Soon, scientists inacademia, pharmaceutical companies, and regulatory agencies realized that character-ization of the metabolic fate of drugs was an important component in understandingtheir clinical profiles. Initially, it was sufficient to merely demonstrate that a doseddrug and/or its metabolites were eliminated from the body in a reasonable amount oftime. Next, in the evolution of drug metabolism, there was a need to determine thechemical form of the major drug-related materials in the excreta. Today, the potentialrole of circulating metabolites in therapeutic action as well as toxicity has becomeapparent, and a sophisticated quantitative chemical, biochemical, pharmacological,and toxicological description of metabolism is required for the registration of newdrugs.Finally, we can ask “What is the object of drug metabolism?” As can be seen insubsequent sections, drug metabolism is more than just an attempt by the body to “eat”ingested foreign compounds. The existence of a complex, regulated, and interacting setof barriers and CL mechanisms suggests that the object is to chemically and physicallylimit the entry of these compounds to the body and facilitate their removal from thebody. Those compounds that are not clearable by direct excretion in urine or feces aresubject to sequential rounds of metabolism, which change their chemical and physicalproperties until theycanbe excreted. With these thoughts in mind, let us discuss indetail exactly what drug metabolism is and why it is important to the discovery anddevelopment of new drugs.1.3THE PHENOMENON OF DRUG METABOLISMDrug metabolism comprises such a rich variety of chemical modifications of organiccompounds that it is rare to find a drug that is not subject to some type of metabolicprocess. Of course, there is a kinetic component of the drug-metabolism process aswell, so in some cases the metabolism occurs only slowly. For example, amiodaroneis cleared from the body exclusively by metabolism [3], but because the metabolicprocess is very slow, this drug has a 55-day terminal half-life [4]. In other cases, thedirect excretion process is much faster than metabolism and dominates CL. So we findthat amoxicillin, for example, is mainly excreted as the intact parent drug in urine [5].Nonetheless, most drugs are rapidly metabolized as the major route of CL from thebody. Although the diverse manifold of possible reactions presents a complex array of4REVIEW OF DRUG METABOLISM IN DRUG DISCOVERY AND DEVELOPMENTpossibilities, we can recognize some patterns, so that it is possible to use relatively fewterms to describe virtually all the transformations. In fact, there are only four majorcategories: oxidations, reductions, conjugations, and hydrolyses.These four categories of chemical transformation arise from four broad classesof enzymes, which actually accomplish the transformation for a particular drug. It iscommon, if not universal, for a particular drug to be subject to more than one metabolicconversion. For example, dextromethorphan has two major metabolites, one resultingfrom N-demethylation and the other from O-demethylation (Fig. 1.1).As one would expect, some metabolites are the product of sequential operation oftwo or more of these basic transformations, as shown for loratadine, which under-goes oxidative decarboethoxylation followed by aromatic hydroxylation and finallyglucuronidation (Fig. 1.2).Occasionally, a metabolic pathway apparently not conforming to this fourfold cat-egorization is encountered, as shown in Fig. 1.3.However, almost always, closer examination shows that the process was actually adiversion during operation of one of the four standard categories [8,9]. In the examplein Fig. 1.3, pulegone is first hydroxylated on an allylic methyl group, followed byinternal hemiketal formation and dehydrative aromatization to form menthofuran [10].H3COH3CO+HONCH3NHNCH3Figure 1.1N- and O-demethylation of dextromethorphan [6].ClNNClNCO2EtNHHOOCHOHOOOHONClHONClNHNHFigure 1.2Metabolic pathway for loratadine [7].THE PHENOMENON OF DRUG METABOLISMOO5Figure 1.3Ring closure of pulegone to menthofuran.H3CONF3CCH3CH3F3CNH3CNNOCH3H3CONCH3CH3NH3COCH3N NOHNNFigure 1.4Ring contraction of vicriviroc [11].A more vexing example is provided below by the contraction of a six-memberedpyrimidine ring to a five-membered pyrazole ring in the anti-HIV drug vicriviroc(Fig. 1.4). Although no explanation for this reaction had been published, one canwrite a plausible, albeit complex, metabolic pathway linking the parent drug and themetabolite utilizing only known reactions from the four standard categories (detailsleft as an exercise for the reader).Although many interesting chemical transformations are known in biochemistry, welimit our discussion here only to ones that have been demonstrated to occur with xeno-biotics. Table 1.1 summarizes the main chemical reactions of human drug metabolism.Each metabolic reaction has been given a name descriptive of the overall chemicaltransformation that occurs, regardless of the internal mechanism by which the trans-formation was accomplished. However, in many cases, the metabolic reaction has aname commonly used in the published literature of drug metabolism. For example,“introduction of an oxygen atom at an aliphatic position” would typically be referredto asHydroxylation,even though an oxygen atom, not a hydroxyl group was addedto the molecule. The common name is given in parenthesis. Note that the drugs andmetabolites are drawn in their unionized forms to better see the chemical transforma-tion that has occurred. Although Table 1.1 is intended to be reasonably comprehensivefor introductory purposes, it is not exhaustive. A number of unusual examples havebeen compiled elsewhere [8,9].Finally, it is worth noting that some metabolic reactions can be reversed, leadingto the phenomenon offutile cycling.A metabolite that is produced through one of themetabolic reactions in Table 1.1 may be reconverted to the parent drug by anothermetabolic reaction, with no net chemical transformation. An example is the conver-sion of a tertiary amine to anN-oxide(Reaction I.F). Since someN-oxidescan bereduced to tertiary amines (Reaction II.B), the result is that the amine appears not tohave been metabolized, when in fact two metabolic steps occurred [32]. The existence [ Pobierz całość w formacie PDF ]