1. Medicinal Chemistry-I By Dr. Mehnaz Kamal Assistant Professor Pharmaceutical Chemistry Prince Sattam Bin Abdulaziz University

2. DRUGMETABOLISM

3. The Fate of a Drug

5. BIOTRANSFORMATION/METABOLISM OF DRUGS  Chemical modification of drugs or foreign compounds (xenobiotics) in the body.  The apparent function of drugs or xenobiotics metabolism is their transformation into water- soluble derivative which can be easily eliminated via renal route.

6. Effect of drug metabolism Active drugInactive Drug Active drug Inactive prodrug Inactive metabolite Metabolic activation  Lipid Solubility R-H R-OH Chemical hook

7.  Drug metabolism reactions traditionally have been regarded as detoxification processes. However, it is incorrect to assume that drug metabolism reactions are always detoxifying.  It is becoming increasingly clear that not all metabolites are nontoxic. Many toxic side effects of drugs and environmental contaminants can be attributed directly to the formation of chemically active metabolites that are highly detrimental to the body.

8. Implications For Drug Metabolism 1.Termination of drug action 2.Activation of prodrug 3.Bioactivation and toxication 4.Carcinogenesis  The objective of studying drug metabolism is to make medicinal chemists aware of the chemical processes involved in the biotransformation of drugs and to encourage them to further study so as to be able to use the acquired knowledge in the design of new more safe drugs.

9.  Two categories of xenobiotics are not or are hardly subject to metabolic transformations : 1- Hydrophilic compounds (e.g. saccharine, strong acids or bases) 2- Highly lipophilic polyhalogenated xenobiotics such as some insecticides e.g. DDT.

10.  Innumerable examples exist of metabolic reactions not leading to inactivation and detoxication.  Some metabolite will possess its own activity which will be similar to or different from that of the parent drug.  Other metabolites may be highly reactive entities able to bind covalently to soluble or membrane proteins, enzymes, or even DNA (mutagenic and carcinogenic compounds).

11. Lethal synthesis:  Lethal synthesis: a classic example of lethal synthesis is provided by the metabolic conversion of the nontoxic insecticide parathion into its oxygenated isostere paraoxon, a potent acetylcholinesterase inhibitor

12. Major Sites of Metabolism Major Sites of Metabolism  Drug metabolism can occur in every tissue (e.g. gut, lung, kidney). However, the major drug metabolizing enzymes (DMEs) are expressed at the highest levels in the liver, which serves as the major organ of metabolic clearance High liver Mediumlung, kidney, intestine Lowskin, testes, placenta, adrenals Very lownervous system

13. Hepatic microsomal enzymes (oxidation, conjugation) Extrahepatic microsomal enzymes (oxidation, conjugation) Hepatic non-microsomal enzymes (acetylase, sulfate transferase, GSH S-transferase, alcohol/aldehyde dehydrogenase, hydrolase, oxidase/reductase)

14.  The LIVER is the chief organ for drug metabolism because: – The blood flow through the liver is high – Hepatocytes contain numerous metabolic enzymes

15.  Biotransformation broadly classified into two types of reactions: PHASE I – PHASE I: Functionalization reaction, new polar groups such as CO 2 H, OH or NH 2 are introduced or unveiled/unmasked from pre-existing functions through oxidative, reductive or hydrolytic reactions. PHASE II – PHASE II: known as conjugation reactions, link an endogenous solubilizing moiety either to the original drug (if polar functions are already present) or to the phase I metabolite.

16. Oxidation 1- Oxidation electron removal, dehydrogenation and hydroxylation. Reduction 2- Reduction electron addition, hydrogenation and removal of oxygen 3- Hydrolytic reactions/Hydrolysis  Phase I or Functionalization Reactions

17. OxidationReductionHydrolysis hydroxylations aromatic, aliphatic, nitrogen dealkylations(N-, S-, P) deaminations N-, S-, P- oxidations S-replacements epoxidations others azo reduction nitro reduction disulfide reduction others esters amides oxidoreductases oxidases monoamine oxidases mixed function oxidases oxidoreductases reductases esterases amidases peptidases lipases

18. The great majority of these oxidations are carried out by the haemoprotein cytochrome P- 450 which is embedded within the phospholipid environment of the microsomes derived from the endoplasmic reticulum of living cells. 1. Oxidation reactions Cytochrome P 450 (CYPs) Cytochrome P 450 is a family of enzymes located in the endoplasmic reticulum of liver. When liver is homogenized and biochemically fractionated these enzymes are found in the microsomal fraction (small closed ER membrane fragments). Thus these enzymes are called microsomal enzymes.

19.  Cytochrome P 450 enzymes perform many of the most important biotransformation reactions.  These enzymes oxidize a wide variety of compounds foreign to the body.  There are at least 18 different forms of cytochrome P 450 identified in humans, produced by different genes.  60% of drugs are metabolized primarily by CYPs.

20. Important cytochrome P 450 enzymes: 1. CYP3A4. 2. CYP1A2. 3. CYP2C. 3. CYP2D6. Individual enzymes differ in their substrate specificity and regulatory properties.

21. The reaction sequence illustrated by CyP Redox Cycle : R-H + O 2 + 2e - + 2H + R-OH + H 2 O

22. hydroxylations aromatic, aliphatic, nitrogen dealkylations (N-, S-, P-) deaminations N-, S-, P- oxidations S-replacements epoxidations others oxidation

23. 1.1. Carbon oxidation reactions/ C-oxidation reactions  The reactions of C-oxidation represent the common metabolic attacks on xenobiotics. a) Hydroxylation of saturated aliphatic carbon atoms – In practice a non-activated alkyl group undergoes mainly  and  -1 oxidation  Oxidation occurs at the terminal methyl group  -1 oxidation occurs at the carbon atom next to the last one (penultimate carbon atom)

25.  Cyclic aliphatic systems are usually hydroxylated on the least-hindered or most-activated carbon atoms

26. b) Hydroxylation at activated SP 3 carbon atoms

27.  The final result is dealkylation when a secondary or tertiary amine loses an alkyl substituent, and deamination when the substrate loses an amino group

28.  Aromatic ethers undergo a similar  - hydroxylation, followed by hydrolysis of the hemiacetal to a phenol and aldehyde  Dealkylation reactions can also result from direct oxidation of the heteroatom (N,S) as opposed to that of the  -carbon.

29.  Dehalogenated carbonyl compounds are formed which may lead to toxic reactions.

30. c) Oxidation attack on unsaturated aliphatic systems  Carbon-carbon double bonds undergo metabolic epoxidation to the corresponding epoxide, an alkylating metabolite which can, for example, alkylate nucleic acids

31.  Carbon-Carbon triple bonds, oxygen insertion yields an oxirene which opens by heterolytic C-O bond cleavage to form a highly reactive intermediate which binds covalently to the enzyme.

32. d) Hydroxylation of aromatic rings

33.  As a rule, hydroxylation occurs on the less- hindered site, usually the para- position. Electronic factors are also operative. This can be seen in the following representative examples:

34. 1.2. N-oxidation reactions –Tertiary aliphatic amines are usually oxidized to the corresponding N-oxides, but the reaction is strongly affected by steric hindrance. –Secondary and primary amines are N-oxygenated to hydroxylamines, the intermediate is believed to be an N-oxide.

35.  Methaemoglobinaemia toxicity caused by several aromatic amines, e.g. Dapsone, is attributed to their bioconversion to the corresponding N-hydroxy derivative

36.  Amides can be N-oxygenated to hydroxylamides. The overdose toxicity of Acetaminophen/Paracetamol has been attributed to NAPQI (N-acetyl-p-benzoquinone imine).

38.  S-Oxidation constitutes an important pathway in metabolism of the H 2 -histamine antagonist, Cimetidine. The corresponding sulfoxide derivative is the major metabolite.  Sulfoxide drugs and metabolites (e.g. those of phenothiazines) may be further oxidized to sulfones (-SO 2 -). 1.3. S-oxidation reactions

40. 2. Reduction reactions  It is a major route of metabolism for aromatic nitro and azo compound as well as for a wide variety of aliphatic and aromatic N-oxides which are reduced to tertiary amines.  From a quantitative point of view, reduction reactions are less important than oxidations since the human organism is mostly an aerobic one.

41. 2.1. Reductions at carbon atoms The major reactions of reduction at carbon atoms can be illustrated by the following scheme

42. Various reactions of N-oxidation are reversible, Cyt P450 and other reductases being able to deoxygenate N-oxides back to amine. 2.2. Reductions at other atoms

43. Other reductions involve sulfur and a few other atoms. Thus, disulfides are reduced to thiols, and there are numerous examples of the reduction of sulfoxides to sulphides e.g. sulindac to sulindac sulfide.

44. 3. Hydrolytic reactions/ Hydrolysis  The vast majority of esters and amides may be hydrolyzed in the animal body, the extent and rate of hydrolysis being dependent upon the chemical reactivity of the functional group.  Hydrolysis or hydrolytic cleavage are catalyzed by esterases, peptidases or other enzymes, but non-enzymatic hydrolysis is also known to occur for sufficiently labile compounds under biological conditions of pH and temperature.