Metabolic Changes of Drugs and Related Organic Compounds

Transcription

1 Metabolic Changes of Drugs and Related Organic Compounds 3 rd stage/ 1 st course Lecture 3 Shokhan J. Hamid

2 2 Metabolism plays a central role in the elimination of drugs and other foreign compounds from the body.

3 3 If lipophilic drugs, or xenobiotics, were not metabolized to polar, readily excretable water-soluble products, they would remain indefinitely in the body, eliciting their biological effects. Thus, the formation of water-soluble metabolites not only enhances drug elimination, but also leads to compounds that are generally pharmacologically inactive and relatively nontoxic. drug metabolism reactions have traditionally been regarded as detoxification processes!!!

4 4 General Pathways of Drug Metabolism Drug metabolism reactions have been divided into two categories: phase I, functionalization and phase II, conjugation reactions.

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6 6 Phase I, include oxidative, reductive, and hydrolytic biotransformations. The purpose of these reactions is to introduce a polar functional group(s) e.g., OH, COOH, NH2, SH into the xenobiotic molecule to produce a more water-soluble compound. This can be achieved by direct introduction of the functional group e.g., aromatic and aliphatic hydroxylation or by modifying or un masking existing functionalities e.g., reduction of ketones and aldehydes to alcohols; oxidation of alcohols to acids and etc.. Although phase I reactions may not produce sufficiently hydrophilic or inactive metabolites, they generally tend to provide a functional group on the molecule that can undergo subsequent phase II reactions.

7 7 The purpose of phase II reactions is to attach small, polar, and ionizable endogenous compounds such as glucuronic acid, sulfate, glycine, and other amino acids to the functional groups of phase I metabolites or parent compounds that already have suitable existing functional groups to form water-soluble conjugated products. Conjugated metabolites are readily excreted in the urine and are generally devoid of pharmacological activity and toxicity in humans.

8 8 Other phase II pathways, such as methylation and acetylation, terminate or attenuate biological activity, whereas glutathione (GSH) conjugation protects the body against chemically reactive compounds or metabolites. Thus, phase I and phase II reactions complement one another in detoxifying, and facilitating the elimination of, drugs and xenobiotics.

9 9 Example: The principal psychoactive constituent of marijuana, Δ1- tetrahydrocannabinol. This lipophilic molecule undergoes allylic hydroxylation to give 7- hydroxy-δ1-thc in humans which is more polar than its parent compound. The 7-hydroxy metabolite is further oxidized to the corresponding carboxylic acid derivative. Subsequent conjugation of this metabolite (either at the COOH or phenolic OH) with glucuronic acid leads to water soluble products that are readily eliminated in the urine.

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11 11 In the series of biotransformations, the parent Δ1-THC molecule is made increasingly polar, ionizable, and hydrophilic. The attachment of the glucuronyl moiety (with its ionized carboxylate group and three polar hydroxyl groups to the Δ1-THC metabolites notably favors partitioning of the conjugated metabolites into an aqueous medium. This is an important point in using urinalysis to identify illegal drugs.

12 12 Sites of Drug Biotransformation Although biotransformation reactions may occur in many tissues, the liver is, by far, the most important organ in drug metabolism. Because it is: well-perfused organ. particularly rich in almost all of the drug-metabolizing enzymes. Another important site, especially for orally administered drugs, is the intestinal mucosa, which contains the CYP3A4 isozyme and P-glycoprotein that can capture the drug and secrete it back into the intestinal tract.

13 13 Orally administered drugs that are absorbed into the bloodstream through the GI tract must pass through the liver before being further distributed into body compartments. Therefore, they are susceptible to hepatic metabolism known as the first-pass effect before reaching the systemic circulation. Depending on the drug, this metabolism can sometimes be quite significant and results in decreased oral bioavailability. For example, in humans, several drugs are metabolized extensively by the first-pass effect, the following list includes some of those drugs: Isoproterenol, Morphine, Propoxyphene, Lidocaine, Nitroglycerin, Propranolol, Meperidine, Pentazocine and Salicylamide. Lidocaine, is removed so effectively by first-pass metabolism that they are ineffective when given orally and Nitroglycerin is administered buccally to bypass the liver.

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15 15 Because most drugs are administered orally, the intestine appears to play an important role in the extra hepatic metabolism of xenobiotics. Esterases and lipases present in the intestine may be particularly important in carrying out hydrolysis of many ester prodrugs. Bacterial flora present in the intestine appear to play an important role in the reduction of many aromatic azo and nitro drugs (e.g., sulfasalazine). Intestinal β-glucuronidase enzymes can hydrolyze glucuronide conjugates excreted in the bile, thereby liberating the free drug or its metabolite for possible reabsorption (enterohepatic circulation or recycling).

16 16 Role of Cytochrome P450 Monooxygenases in Oxidative Biotransformations Of the various phase I reactions, oxidative biotransformation processes are, by far, the most common and important in drug metabolism. The oxidation of many xenobiotics (R-H) to their corresponding oxidized metabolites (R-OH) is given by the following equation: RH + NADPH + O2 + H+ ROH + NADP+ + H2O The enzyme systems carrying out this biotransformation are referred to as mixed-function oxidases or monooxygenases. The reaction requires both molecular oxygen and the reducing agent NADPH (nicotinamide adenosine dinucleotide phosphate). During this oxidative process, one atom of molecular oxygen (O2) is introduced into the substrate R-H to form R-OH and the other oxygen atom is incorporated into water

17 17 The mixed-function oxidase system is actually made up of several components, the most important being the superfamily of CYP enzymes which are responsible for transferring an oxygen atom to the substrate R-H. The CYP enzymes are heme proteins, the heme portion is an ironcontaining porphyrin called protoporphyrin IX, and the protein portion is called the apoprotein. CYP is found in high concentrations in the liver, the major organ involved in the metabolism of xenobiotics. The presence of this enzyme in many other tissues (e.g., lung, kidney, intestine, skin, placenta, adrenal cortex) shows that these tissues have drug-oxidizing capability too.

18 18 The name cytochrome P450 is derived from the fact that the reduced (Fe +2) form of this enzyme binds with carbon monoxide to form a complex that has a distinguishing spectroscopic absorption maximum at 450 nm. One important feature of the hepatic CYP mixed function oxidase system is its ability to metabolize an almost unlimited number of diverse substrates by various oxidative transformations. The CYP monooxygenases are located in the endoplasmic reticulum, a highly organized and complex network of intracellular membranes that is particularly abundant in tissues such as the liver.

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20 A. OXIDATIVE REACTIONS

21 21 1. Oxidation of Aromatic Moieties: Aromatic hydroxylation refers to the mixed-function oxidation of aromatic compounds arenes to their corresponding phenolic metabolites arenols. Almost all aromatic hydroxylation reactions are believed to proceed initially through an epoxide intermediate called an arene oxide, which rearranges rapidly and spontaneously to the arenol product in most instances.

22 22 Arene oxide intermediates are formed when a double bond in aromatic moieties is epoxidized. Arene oxides are of significant toxicologic concern because these intermediates are electrophilic and chemically reactive. Arene oxides are mainly detoxified by spontaneous rearrangement to arenols, but enzymatic hydration to trans-dihydrodiols by epoxide hydrase enzyme and enzymatic conjugation with GSH by GSH S-transferase also play very important roles. If not effectively detoxified by these three pathways, arene oxides will bind covalently with nucleophilic groups present on proteins, DNA, and RNA, thereby leading to serious cellular damage.

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24 24 In humans, aromatic hydroxylation is a major route of metabolism for many drugs containing phenyl groups. Important therapeutic agents such as propranolol, phenobarbital, phenytoin, phenylbutazone,atorvastatin, 17-ethinylestradiol, and (S)(-)-warfarin, undergo extensive aromatic oxidation. In most of the drugs just mentioned, hydroxylation occurs at the para position. Most phenolic metabolites formed from aromatic oxidation undergo further conversion to polar and water soluble glucuronide or sulfate conjugates, which are readily excreted in the urine.

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26 The para-hydroxylated metabolite of phenylbutazone, is pharmacologically active and has been marketed itself as an anti-inflammatory agent. 26

27 27 The two enantiomeric forms of the oral anticoagulant warfarin (Coumadin), only the more active S(-) enantiomer has been shown to undergo substantial aromatic hydroxylation to 7- hydroxywarfarin in humans. In contrast, the (R)(+) enantiomer is metabolized by keto reduction.

28 28 The substituents attached to the aromatic ring may influence the ease of hydroxylation. Aromatic hydroxylation reactions appear to proceed most readily in activated (electron-rich) rings, whereas deactivated aromatic rings (e.g., those containing electron-withdrawing groups Cl, -NR3, COOH, and etc.. are generally slow or resistant to hydroxylation. The deactivating groups present in the antihypertensive clonidine may explain why this drug undergoes little aromatic hydroxylation in humans.

29 The uricosuric agent probenecid, with its electronwithdrawing carboxy and sulfamido groups, has not been reported to undergo any aromatic hydroxylation. 29

30 30 In compounds with two aromatic rings, hydroxylation occurs preferentially in the more electron-rich ring. For example, aromatic hydroxylation of diazepam (Valium) occurs primarily in the more activated ring to yield 4-hydroxydiazepam. A similar situation is seen in the 7-hydroxylation of the antipsychotic agent chlorpromazine and in the para-hydroxylation of p-chlorobiphenyl to p-chloro-p-hydroxybiphenyl.

31 31 Recent environmental pollutants, such as polychlorinated biphenyls (PCBs) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), have attracted considerable public concern over their toxicity and health hazards. These compounds appear to be resistant to aromatic oxidation because of the numerous electronegative chlorine atoms in their aromatic rings. The metabolic stability coupled to the lipophilicity of these environmental contaminants probably explains their long persistence in the body once absorbed

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