Podcast
Questions and Answers
A ketone is reduced to what type of alcohol?
A ketone is reduced to what type of alcohol?
What enzyme is primarily responsible for the reduction of carbonyl compounds?
What enzyme is primarily responsible for the reduction of carbonyl compounds?
What is the major type of metabolites produced upon the reduction of nitro compounds?
What is the major type of metabolites produced upon the reduction of nitro compounds?
Which of the following compounds undergoes extensive reduction to generate its alcohol form?
Which of the following compounds undergoes extensive reduction to generate its alcohol form?
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Reduction of which functional group leads to sulfoxides?
Reduction of which functional group leads to sulfoxides?
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What is the minimum requirement the FDA generally asks of sponsors regarding toxicity testing?
What is the minimum requirement the FDA generally asks of sponsors regarding toxicity testing?
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What is the primary purpose of Phase I clinical trials?
What is the primary purpose of Phase I clinical trials?
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In which phase does the FDA primarily assess the drug's safety and effectiveness over a longer duration?
In which phase does the FDA primarily assess the drug's safety and effectiveness over a longer duration?
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What is an Orphan Drug designed to treat?
What is an Orphan Drug designed to treat?
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What happens after the completion of clinical trials in the drug development process?
What happens after the completion of clinical trials in the drug development process?
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Study Notes
Toxicity Testing
- In vitro and in vivo testing are essential for evaluating drug safety.
- LD50 (lethal dose for 50% of the population) helps determine acute toxicity.
- FDA requires a pharmacological profile of the drug from sponsors.
- At least two species of animals must be used for acute toxicity studies.
- Short-term toxicity studies should last between 2 weeks and 3 months, depending on intended use.
Drug Development Process
- IND (Investigational New Drug) Application must be filed before human clinical trials.
- Special consideration for Orphan Drugs, treating diseases affecting fewer than 200,000 people in the US.
- NDA (New Drug Application) is submitted post-clinical trials for FDA review.
Clinical Trials Phases
- Phase I: 20-100 patients for several months; focuses on safety. Success rate: 67%.
- Phase II: Several hundred patients for several months to 2 years; assesses short-term safety and effectiveness. Success rate: 45%.
- Phase III: Several hundred to several thousand patients over 1-4 years; evaluates safety, effectiveness, and dosage. Success rate: 5-10%.
Drug Metabolism
- Reductions convert carbonyl compounds; ketones to secondary alcohols, aldehydes to primary alcohols.
- Aldo-keto reductases are responsible for reducing substances like warfarin.
- Nitro and azo compounds reduce to primary amines; examples include clonazepam and metronidazole.
Phase I Reactions
- Hydroxyl and amino groups prone to conjugation.
- GSH (glutathione) protects against reactive species, forming mercapturic acid derivatives.
Phase II Reactions
- Include acetylation, important for detoxification of primary amines.
- Methylation is crucial for the biosynthesis and inactivation of compounds like catecholamines.
Factors Affecting Drug Metabolism
- Age differences impact enzyme activity; newborns may experience gray-baby syndrome due to enzyme deficiencies.
- Genetic polymorphisms lead to variability in metabolic rates across individuals and species.
- Species and strain differences affect metabolic pathways; e.g., rats metabolize aromatics differently than humans.
Diseases Affecting Metabolism
- Thyroid dysfunction can compromise metabolic processes, affecting drug efficacy and safety.
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Description
Explore the essential principles of toxicity testing, including both in vitro and in vivo methodologies. Understand the determination of LD50 and the requirements set by the FDA for pharmacological profiling and acute toxicity assessment of new drugs.
