Drug Metabolism and Excretion

• Metabolism plays a central role in eliminating drugs and foreign compounds (xenobiotics) from the body
• Most organic compounds entering the body are lipid soluble (lipophilic)
• Compounds must traverse the lipoprotein membranes of the lumen walls of the gastrointestinal (GI) tract to be absorbed
• Once in the bloodstream, molecules passively diffuse through membranes to reach target organs and exert pharmacological actions
• Lipophilic compounds are not excreted to any substantial extent in the urine due to reabsorption in the renal tubules
• Xenobiotics undergo metabolic fate through enzyme systems, changing the parent compound to become more water-soluble (hydrophilic)
• A sufficiently water-soluble metabolite may be excreted from the body
• Lipophilic drugs/xenobiotics not metabolized to polar, readily excretable water-soluble products remain indefinitely in the body, eliciting biological effects
• Formation of water-soluble metabolites enhances drug elimination and leads to pharmacologically inactive, nontoxic compounds
• Detoxication processes are drug metabolism reactions
• Drug metabolism reactions are not always detoxifying
• Drugs are biotransformed to pharmacologically active metabolites with significant pharmacological/toxicological effects attributed to the parent drug
• Some parent compounds are inactive when administered and must be converted metabolically to a biologically active drug (metabolite), known as prodrugs
• Adverse effects like tissue necrosis, carcinogenicity, and teratogenicity can be attributed to the formation of chemically reactive metabolites
• Disease states that inhibit/accelerate xenobiotic metabolism are important considerations

Purpose of Metabolism in Relation to Drug Molecules

• Metabolism can serve to inactivate a drug
• Isoniazid, an antituberculosis drug, can be inactivated by acetylation, adding an acetyl derivation to produce an inactive compound
• Metabolism maintains or enhances drug activity
• Diazepam undergoes several steps of metabolism (demethylation of amine, hydroxylation of the 3rd position) to convert it from an active compound to a more active form
• Metabolism initiates the activity of some drugs
• Prodrugs are inactive when administered but activated inside the body
• Enalapril, taken in ester form, undergoes deesterification in the liver to become active

General Pathways of Drug Metabolism

• Drug metabolism reactions are divided into phase I (functionalization) and phase II (conjugation) reactions

• Phase I (Functionalization) Reactions:

• Include oxidative, reductive, and hydrolytic biotransformations

• Introduce a functional polar group(s) (e.g., OH, COOH, NH2, SH) into the xenobiotic molecule

• Achieved through:

• Direct introduction of the functional group (e.g., aromatic and aliphatic hydroxylation)

• Modifying/ "unmasking" existing functionalities, such as reducing ketones/aldehydes to alcohols, oxidizing alcohols to acids, hydrolysis of esters/amides to yield COOH/NH2/OH groups, reducing azo/nitro compounds to give NH2 moieties, and oxidative N-, O-, and S-dealkylation to give NH2/OH/SH groups

• Phase I reactions may not produce sufficiently hydrophilic or inactive metabolites

• Phase I reactions tend to provide a functional group for subsequent phase II reactions

• Phase II Reactions:

• Form water-soluble conjugated products by attaching small, polar, ionizable endogenous compounds (glucuronic acid, sulfate, glycine, other amino acids) to phase I metabolites

• Conjugated metabolites are readily excreted in the urine and generally devoid of pharmacological activity and toxicity in humans

• Other phase II pathways:

• Methylation and acetylation terminate/attenuate biological activity

• Glutathione (GSH) conjugation protects the body against chemically reactive compounds or metabolites

• Phase I and phase II reactions complement one another in detoxifying and eliminating drugs/xenobiotics

Sites of Drug Biotransformation:

• The liver is the most important organ in drug metabolism and detoxification
• It is a well-perfused organ rich in almost all drug-metabolizing enzymes
• Orally administered drugs absorbed into the bloodstream through the GI tract pass through the liver before distribution
• Drugs are susceptible to hepatic metabolism (first-pass effect) before reaching systemic circulation, which can decrease oral bioavailability depending on the drug
• Examples of drugs extensively metabolized by the first-pass effect in humans: Isoproterenol, Morphine, Propoxyphene, Lidocaine, Nitroglycerin, Propranolol, Meperidine, Pentazocine, and Salicylamide
• The intestinal mucosa is another site important for orally administered drugs
• It contains CYP3A4 isozyme and P-glycoprotein, which can capture and secrete the drug back into the intestinal tract
• Orally administered isoproterenol undergoes considerable sulfate conjugation in the intestinal wall
• Levodopa, chlorpromazine, and diethylstilbestrol are also metabolized in the GI tract
• Esterases and lipase in the intestine are important in hydrolyzing many ester prodrugs
• Bacterial flora in the intestine/colon reduce many aromatic azo and nitro drugs
• Intestinal-glucuronidase enzymes hydrolyze glucuronide conjugates excreted in bile, liberating free drug/metabolite for possible reabsorption (enterohepatic circulation/recycling)
• Other tissues (kidney, lungs, adrenal glands, placenta, brain, skin) have some drug metabolizing capability but are more substrate selective and limited to particular reaction types (oxidation and glucuronidation)

Role of Cytochrome P450 Monooxygenase in Oxidative Biotransformation:

• Oxidative biotransformation processes are the most common and important in drug metabolism
• Enzyme systems carrying out this biotransformation are called mixed-function oxidases or monooxygenases
• Nomenclature of these enzymes has four components: CYP (cytochrome system), a number (cytochrome family), a capital letter (subfamily), and another number (specific enzyme for a reaction)
• The reaction requires molecular oxygen and the reducing agent NADPH
• One oxygen atom is introduced into the substrate R-H to form R-OH, and the other oxygen atom is incorporated into water
• The mixed-function oxidase system is made of several components, including the CYP oxidase enzymes responsible for transferring an oxygen atom to the substrate RH
• Other important components include NADPH-dependent CYP reductase and NADH-linked cytochrome b5
• These components, with cofactors NADPH and NADH, supply reducing equivalents (electrons) for the overall metabolic oxidation of foreign compounds
• CYP enzymes are heme proteins with an iron-containing porphyrin called protoporphyrin IX and a protein called apoprotein
• CYP is highly concentrated in the liver, the major organ involved in xenobiotic metabolism
• Presence in other tissues (lung, kidney, intestine, skin, placenta, adrenal cortex) indicates drug-oxidizing capability
• 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 with a distinguishing spectroscopic absorption maximum at 450 nm
• Hepatic CYP mixed function oxidase system can metabolize almost an unlimited number of diverse substrates by various oxidative transformations.
• This is due to the substrate non-specificity of CYP and the presence of multiple forms of the enzyme
• Some P450 enzymes are selectively inducible by various chemicals