Pharmaceutical and Medicinal Organic Chemistry - Drug Metabolism

Flashcards for Pharmaceutical and Medicinal Organic Chemistry focusing on drug metabolism.

Metabolism

Plays a central role in the elimination of drugs and other foreign compounds; most drugs are relatively lipid soluble and need to be metabolized to polar, water-soluble products to be excreted.

Active Metabolites

Retain the same pharmacologic activity of the parent drug.

Inactive Metabolites

Do not retain the pharmacologic activity of the parent drug.

Bioactivation

Inactive parent compound is transformed to an active metabolite.

Drug Metabolism

Can result in decreased pharmacological activity, increased pharmacological activity, increased toxicity, or altered pharmacological activity of a drug.

Liver

Most important organ in drug metabolism, rich in almost all drug metabolizing enzymes.

First-Pass Metabolism

Drug absorbed into the hepatic portal system and, if lipophilic enough, will gain access to hepatocytes.

Pre-systemic Metabolism

Gut mucosa is rich in oxidizing enzymes and conjugating transferase enzymes which can deactivate the drug before it ever gets absorbed.

Genetic Factors/Hereditary

Individual metabolism can be affected by the genetic expression of the many metabolizing enzymes (polymorphisms).

Pharmacogenomics and Pharmacogenetics

The genomic and genetic differences between racial and ethnic groups that have different levels of gene expression and enzyme levels which can lead to very different drug responses between individuals.

Physiologic Factors (Age)

Age is a factor since the very young and the very old have impaired metabolism.

Physiologic Factors (Placenta)

There are a number of important metabolizing enzymes in the placenta helping to protect the fetus.

Physiologic Factors (Gender)

Gender differences in metabolism between men and women, although not clearly understood, might be associated with hormonal differences which can lead to different levels of inducible oxidizing enzymes (CYP3A4).

Pharmacodynamic Factors

Dose, frequency, and route of administration, plus tissue distribution and protein binding of a drug may affect its metabolism.

Environmental Factors

Ingested or inhaled environmental substances can compete for metabolizing enzymes, induce, or inhibit enzymes, or even poison enzymes.

Drug-Drug Interactions

Drug-drug, drug-food, and drug-herbal interactions are common clinical problems.

Metabolism-Based Drug-Drug Interactions

Competition between two drugs for the enzyme-active site.

Mechanism-Based Drug-Drug Interactions

The inhibitory effect of the drug only occurs after an activation step producing an active inhibitor

Grapefruit Juice

Can significantly increase the oral bioavailability of drugs that are metabolized by CYP3A4 in the intestinal tract.

Enzyme Induction

accelerates drug metabolism, results in decrease in pharmacologic action of drug inducer and co-administered drugs, in case of prodrugs = increased toxicity

Enzyme Inhibition

CYP450 enzyme activity is inhibited, reduced metabolism of co-administered drugs and other endogenous substances.

Classifications of Drug Metabolism

Divided into two phases: Phase 1 and Phase 2.

Phase I Drug Metabolism

Functionalization reactions; purpose: provide a polar functional group or 'handle' to the drug molecule. The goal is to increase polarity, increase excretion. Processes include oxidation, reduction, hydrolysis

Oxidation

Most common and most important in drug metabolism.

Microsomal Mixed Function Oxidase System Activity

Requires: reducing agent (NADPH), molecular oxygen (O2).

Peroxidases and other Monooxygenases

Bare heme proteins closely related to CYP450 but differing in the nonporphyrin coordinating ligands.

Oxidases and dehydrogenases

Found in mitochondrial and soluble fractions of tissue homogenates.

Alcohol Dehydrogenases (ADHs)

A family of nicotinamide adenine dinucleotide (NAD)-specific dehydrogenases.

Aldehyde Dehydrogenases (ALDHs)

A family of polymorphic NAD-specific dehydrogenases that oxidize aldehydes to carboxylic acids.

Aldehyde Oxidase (AO)

A molybdenum cofactor-specific enzyme that generates carboxylic acids and hydrogen peroxide from aldehydes in the presence of oxygen.

Xanthine Oxidase and Xanthine Dehydrogenase

Involved in purine metabolism converting hypoxanthine to uric acid.

Monoamine Oxidase (MAO)

A mitochondrial membrane flavin-containing enzyme that catalyzes the oxidative deamination of monoamines.

CYP450 Enzymes

A superfamily of oxidases that is responsible for the majority of oxidative processes and consists of heme-containing enzymes.

Classification of CYP450 - Family of Genes

Arabic numeral designating the family member (e.g., CYP1, CYP2, CYP3, etc.).

Classification of CYP450 - Subfamily

Capitalized letter denoting the subfamily (e.g., CYP1A, CYP2C, CYP3A, etc.).

Classification of CYP450 - Individual Gene

Arabic numeral identifying the individual gene (e.g., CYP1A1, CYP2D6, CYP3A4, etc.).

CYP450 Cycle

Most common sequence of drug oxidation.

Oxidation of Aromatic Moieties

Aromatic compounds are oxidized to their corresponding phenolic metabolites, which is a major route of metabolism for many drugs containing phenyl groups, and produce an intermediate called arene oxide

Oxidation of Olefins

leads to formation of epoxides which are more stable than arene oxides.

Oxidation at Benzylic Carbon Atoms

Carbon atoms attached to aromatic rings are susceptible to oxidation forming the alcohol or carbinol metabolites.

Allylic Carbon

Carbon atom bonded to a carbon atom that in turn is doubly bonded to another carbon atom.

Alpha Carbon

First carbon that attaches to a functional group.

Aliphatic Carbon

Carbon atoms are linked in open chains, either straight or branched, rather than containing a benzene ring.

Alicyclic Carbon

Both aliphatic and cyclic.

w-oxidation

Oxidation at terminal methyl group.

w-1 oxidation

Oxidation at penultimate carbon atom.

Carbon-Nitrogen Systems

Oxidative N-dealkylation of tertiary aliphatic and alicyclic amines.

Carbon-Oxygen Systems

Oxidative O-dealkylation of carbon-oxygen systems is catalyzed by monooxygenases.

Carbon-Sulfur Systems

Susceptible to: S-dealkylation, desulfuration, and S-oxidation reactions.

Reduction

Play an important role in the metabolism of compounds containing carbonyl, nitro, and azo groups

Ester hydrolysis

carried out by: nonspecific esterases, pseudocholinesterases.

Amide hydrolysis

carried out by: amidases, esterases, deacylases.

Phase II Drug Metabolism - Conjugation Reactions

Convert Phase I metabolites into more polar and water-soluble products; terminate or attenuate pharmacologic activity.

Glucuronidation

The most common conjugative pathway; readily available supply of D-glucuronic acid; numerous functional groups can combine enzymatically with glucuronic acid; greatly increase the water solubility of the conjugated product

Sulfate Conjugation

Pathway developed in neonates and young children; conjugate endogenous compounds.

Glycine and Glutamine Conjugation

Used by mammalian systems to conjugate carboxylic acids.

Glutathione/Mercaptopuric Acid Conjugation

An important pathway by which chemically reactive electrophilic compounds are detoxified

Acetylation

Terminates activity of the drug and detoxification.

Methylation

A minor pathway that leads to nonpolar and inactive metabolites; biosynthesis of many endogenous compounds