hon p.1 [100%] YAKUGAKU ZASSHI 130(10) 1325―1337 (2010) 2010 The Pharmaceutical Society of Japan 1325 ―Review― Pharmacologically Active Metabolites of Currently Marketed Drugs: Potential Resources for New Drug Discovery and Development Myung Joo KANG, Woo Heon SONG, Byung Ho SHIM, Seung Youn OH, Hyun Young LEE, Eun Young CHUNG, Yesung SOHN,andJaehwiLEE Division of Pharmaceutical Sciences, College of Pharmacy, Chung-Ang University, 221 Heuksuk-dong, Dongjak-gu, Seoul 156756, South Korea (Received April 14, 2010; Accepted July 14, 2010) Biotransformation is the major clearance mechanism of therapeutic agents from the body. Biotransformation is known not only to facilitate the elimination of drugs by changing the molecular structure to more hydrophilic, but also lead to pharmacological inactivation of therapeutic compounds. However, in some cases, the biotransformation of drugs can lead to the generation of pharmacologically active metabolites, responsible for the pharmacological actions. This review provides an update of the kinds of pharmacologically active metabolites and some of their individual phar- macological and pharmacokinetic aspects, and describes their importance as resources for drug discovery and develop- ment. Key words―pharmacologically active metabolite; biotransformation; metabolism; drug discovery gents exhibited by biotransformation can sometimes INTRODUCTION lead to the generation of pharmacologically active Xenobiotics are chemical substances found in living metabolites, which can responsible for the pharmaco- being but not normally produced or present in body, logical responses.1,46) It has been reported that about including pollutants, dietary components and drugs. 22％ of the top 50 drugs prescribed in the USA in To defense the body against xenobiotic substances, an 2003 undergo biotransformation into metabolites array of biotransformation reactions (or metabolic that play signiˆcant roles in the pharmacological ac- reactions) is undergone. Due to the biotransforma- tions of the corresponding drugs.6) Active metabolites tion, the molecular structure of a drug is commonly exerting improved pharmacological, pharmacokinetic changed to be more hydrophilic and the substances behaviors or lower toxicity than its parent drug were can be readily eliminated from the body.1) already developed as new drugs in some cases. Biotransformation reactions are usually divided In this regard, recognizing the pharmacologically into two broad categories known as phase I and phase active metabolites as signiˆcant resources for drug de- II reactions. In the phase I reaction mediated by en- velopment would be beneˆcial. This paper provides zymes such as cytochrome P450 (CYP), ‰avin-con- an update on pharmacological active metabolites with taining monooxygenase, esterases and amidases, po- their pharmacological and pharmacokinetic aspects, lar functional groups are introduced into the molec- and further describes their values as resources for ules, aŠording it a suitable substrate for direct excre- drug discovery and development. tion. On the other hand, the phase II metabolism, FORMATION OF PHARMACOLOGICALLY AC- mediated by enzymes such as glucuronosyltrans- TIVE METABOLITES ferase, sulfotransferase and N-acetyltransferase, causes conjugation of phase I metabolites or xeno- Pharmacologically active metabolites are generated biotics with highly water-soluble endogenous materi- through mainly primary and/or secondary, and ter- als such as glucuronic acid, sulfate, amino acids or tiary metabolism by phase I and phase II reactions. glutathione.2) After this metabolic process, the drugs Although metabolites are chemical structurally diŠer- are excreted through the bile route.1,3) ent from the parent drug, if they have structural However, the structural alteration of therapeutic a- similarities to the parent molecules, they might attain biological activities similar to the parent drug in some e-mail: jaehwi＠cau.ac.kr cases.6) Table 1 lists the active metabolites produced hon p.2 [100%] 1326 Vol. 130 (2010) from currently marketed drugs. As shown in Table 1, metabolites have more hydrophilic property and bet- simple reactions mediated via CYP generate active ter in vivo metabolic stability compared to their cor- metabolites in many cases such as aromatic or responding parent molecules.1,5,6) Although active aliphatic hydroxylation, O-orN-dealkylation, and metabolites have structural similarities to the parent dehydrogenation or in combinations.1,46) drugs, their protein binding, membrane permeability, Many of the pharmacologically active metabolites tissue distribution, and pharmacological potency are generated via hydroxylation or dealkylation reac- might be diŠerent from those of the parent com- tions. For instance, atorvastatin (Fig. 1(a)),7) pro- pounds. paferone,8) alprazolam,9) atomoxetine,10) ‰utamide,11) The degrees of pharmacological activities of nefazodone,12) acetohexamide,13) cyclosporine,14) metabolites compared to parent drugs are diŠerent propranolol,15) risperidone,16) itraconazole,17) and from each other, but in most cases, metabolites are bupropion (Fig. 1(b))18) generate their active meta- less potent than parent drugs. For instance, 3-hydr- bolites via aromatic or aliphatic hydroxylations. oxyquinidine,37) hydroxymetronidazole,38) (R)-nor- Bupropion also forms two other active metabolites, ‰uoxetine,22,23) norverapamil,39) hydroxycyclospo- namely threohydrobupropion and erythrohydro- rine,14) N-desmethylazonaˆde,26) hydroxybupropion bupropion through carbonyl reduction.18) O-Deme- and threohydrobupropion,18) and many active meta- thylation of venlafaxine (Fig. 1(c)), ivabradine and bolites have weaker activities than their parents. But, artemether gives pharmacologically active O-des- in some cases, metabolites are more potent or have methylvenlafaxine, O-desmethylivabradine and dihy- similar biological activities to parent drugs. 2- or droartemisinin, respectively.1921) Ivabradine also 4-Hydroxyatorvastatin,7) 2-hydroxy‰utamide,11) hy- forms active metabolite by N-demethylation.20) N- droxynefazodone,40) hydroxyacetohexamide,41) 5-hy- Demethylation signiˆcantly contributes to produce droxypropafenone,8) minoxidil sulfate,34) desme- active metabolites in cases of ‰uoxetine (Fig. 1 thylclomipramine,42) mesoridazine,27) (S)-nor‰uoxe- (d)),22,23) sibutramine,24) ferroquine25) and azonaˆde.26) tine,22,23) O-desmethylvenlafaxine19) and S-hydrox- S-Oxidation of thioridazine and epoxidation of car- yrisperidone16) showed comparable activities with bamazepine lead to the formation of mesoridazine27) parent drugs in vitro or vivo experiments. and carbamazepine-10, 11-epoxide,28) respectively. In this part, pharmacological activities and phar- There are also numerous examples of active macokinetic behaviors of active metabolites were il- metabolites that are produced by phase II enzymes. lustrated as follows. Glucuronidation is normally considered to be detox- Acebutolol Acebutolol is a cardioselective be- ifying process, because glucuronides usually possess ta-adrenoreceptor blocking agent. The major meta- less intrinsic biological or chemical activity than their bolite, N-acetyl derivative, diacetolol is pharmacolog- parent forms and exhibit higher polarity and ex- ically active. This metabolite was reported to be e- cretability.29) However, some glucuronide conjugates quipotent to acebutolol in cats and is more cardio- are active and may contribute to pharmacological ac- selective than acebutolol.35) tivities. The N, O-glucuronides of hydroxamic acid30) Acetohexamide Acetohexamide is an oral anti- and the acylglucuronides of carboxylic acids form ac- diabetic drug possessing a moderate duration of ac- tive metabolites.31,32) Particularly, the 6-O-glu- tion. S-Hydroxyacetohexamide and R-hydroxyaceto- curonide of morphine constitutes the most well- hexamide exhibit similar hypoglycemic eŠects in rats. known example of a glucuronide possessing phar- Particularly, S-hydroxyacetohexamide demonstrated macological activity greater than the parent drug.33) a more potent hypoglycemic activity than acetohex- And, the sulfation of minoxidil (Fig. 1(e)), N-acety- amide, implying that S-hydroxyacetohexamide plays lation of acebutol or procainamide has also contribut- an important role in overall hypoglycemic eŠect.13,41) ed the production of the pharmacologically active Both acetohexamide and S-hydroxyacetohexamide metabolites.3436) are rapidly eliminated from the body.43) Alprazolam Alprazolam is a benzodiazepine, PHARMACOLOGICALLY ACTIVE METABO- which is used for the treatment of anxiety, panic dis- LITES OF MARKETED DRUGS orders, depression and sleeping disorders. It is meta- Generally, most of the pharmacologically active bolized to 4-hydroxyalprazolam and 4a-hydroxyal- hon p.3 [100%] No. 10 1327 Table 1. Pharmacologically Active Metabolites of Currently Marketed Drugs Drug Active metabolites Biotransformation Therapeutic actions Atomoxetine 10) 4-Hydroxyatomoxetine Treatment of attention-deˆcit hyperactivity disorder Atorvastatin 7) 2- or 4-Hydroxyatorvastatin Anti-hypercholesterolemia Chlorpromazine 119) 7-Hydroxychlorpromazine Anti-depressive Clomiphene 120) 4-Hydroxyclomiphene Anti-uterotrophic Aromatic hydroxylation Granisetron 121) 7-Hydroxygranisetron Anti-nausea Indapamide 122) 5-Hydroxyindapamide Anti-hypertensive Levamisole 82) 4-Hydroxylevamisole Anthelmintic Propafenone 8) 5-Hydroxypropafenone Anti-arrhythmic Propranolol 15) 4-Hydroxypropranolol Anti-arrhythmic Alprazolam 9) 4-Hydroxyalprazolam Anti-depressant