Drug+Metabolism.pdf

9/10/2024 Drug Metabolism Fadi Khasawneh, Ph.D. (361) 221-0755 [email protected] 1 Learning Outcomes 1. Define drug metabolism (biotransformation). 2. List the two major types/reactions of biotransformation....

9/10/2024 Drug Metabolism Fadi Khasawneh, Ph.D. (361) 221-0755 [email protected] 1 Learning Outcomes 1. Define drug metabolism (biotransformation). 2. List the two major types/reactions of biotransformation. 3. Describe the outcome of drug biotransformation. 4. Understand the relationship between phase I and phase II reactions and provide examples (enzyme name) of each. 2 1  9/10/2024 What is Drug Metabolism The processes by which biochemical reactions alter drugs within the body. Also known as drug biotransformation. The product of this biotransformation is referred to as “metabolite” Liver is the major organ for these processes. These transformations can alter the compound to render it beneficial, harmful, or simply ineffective 3 Drug Metabolism  Many pharmaceuticals are lipophilic, enabling the drug to diffuse across cell membranes, such as those of the intestinal mucosa or of the target tissue.  Unfortunately, the same chemical property that enhances bioavailability of drugs may also make renal excretion difficult, because clearance by the kidney requires that these drugs be made more hydrophilic so that they can dissolve in the aqueous urine. 4 2  9/10/2024 Drug Metabolism (Cont’d)  Not all drugs undergo metabolism, and so those drugs are eliminated/excreted “unchanged” from the body. 5 Drug Metabolism (Cont’d) Drug biotransformation can alter drugs in four important ways: An active drug may be converted to an inactive drug. An active drug may be converted to an active (more or less active than parent drug) or to a toxic metabolite. An inactive prodrug may be converted to an active drug. An unexcretable drug may be converted to an excretable metabolite 6 3  9/10/2024 Prodrugs Prodrugs are inactive compounds/drugs that are metabolized/activated by the body into their active, therapeutic forms. e.g., Plavix® (clopidogrel) 7 Reactions There are two classes of metabolic reactions – Oxidation/Reduction reactions (Phase I) Cytochrome P450 enzymes mediate this process Mainly occurs in the liver – Conjugation/Hydrolysis reactions (Phase II) Attach a “large” (hydrophilic group) molecule to the drug that targets or makes it more amenable to elimination 8 4  9/10/2024 Reactions (Cont’d) The phase I and phase II reactions terminology is imprecise and it incorrectly implies a temporal order of the reaction. A drug does not have to undergo a phase I reaction before it can undergo a phase II reaction. 9 CYP P450s  P450s are a huge family of proteins, each are specialized to metabolize various compounds  Most drugs are metabolized by a few CYPs 10 5  9/10/2024 CYP P450s (Cont’d) Polymorphisms in CYPs can lead to either fast or slow metabolism of drugs – One tool to combat this problem is to determine what polymorphisms a patient harbors  This is important in treatment and is becoming important in drug development 11 CYP P450s (Cont’d) There are three major mammalian families involved in drug (xenobiotic) metabolism. – CYP1 – CYP2 – CYP3 Although some P450 enzymes are constitutively active, others can be induced* or inhibited by various compounds (*increase in their expression) 12 6  9/10/2024 Other Enzymes Other Phase I enzymes include – Alcohol/aldehyde dehydrogenation – Decarboxylation – (Aldehyde) reductases – Hydrolysis enzymes: esterases (hydrolyze ester drugs) 13 Phase II The CYPs, in general, provide a reactive subunit for endogenous transferase enzymes (phase II reactions), which add an endogenous compound to the drug/metabolite Common molecules transferred/added include: – Glucose (Glucuronidation) – Acetate (acetylation) – Glycine (Glycine conjugation) – Sulfate (Sulfate conjugation) – Glutathione (Glutathione conjugation) – Methyl groups (N-, O-, and S-methylation) 14 7  9/10/2024 Phase II (Cont’d) The added groups do two things: – Most groups (not methylation) increase the solubility of the drug in plasma, which facilitates renal elimination D = drug – Multiple transporters recognize the conjugates and thus allow for active transport of the drugs out of the system 15 Hepatic The CYPs are in the liver and this is the organ that does the bulk of the body’s metabolism – Because of this the blood supply leaving the digestive track goes to the liver and then on to the heart This is where the first pass effect comes from, which can either destroy a drug or if using a prodrug, activate a drug 16 8  9/10/2024 Hepatic (Cont’d) Oral medications may go through a 1st pass effect – Must be considered in drug design and pharmaceutics 17 Any questions? The End 18 9