Drug Biotransformation And Excretion

Front 1

site of liver biotransformation

Back 1

parenchymal cells -> hepatocytes

Front 2

organs with high levels of xenobiotic metabolism

Back 2

- liver
- small intestine
- lungs
- kidneys
- nasal epithelium

Front 3

microsomes

Back 3

- smooth endoplasmic reticulum (of liver)
- location of key enzymes involved in drug metabolism (cytochrome P450)
- so called because this is the 100,000 g pellet of the post-mitrochondrial supernatant of the liver homogenate.

Front 4

drug metabolism phases

Back 4

Phase one:
- oxidation
- reduction
- hydroxylation
- dealkylation
- hydrolysis
Phase 2:
- conjugation

Front 5

cytochrome P450 reactions

Back 5

- Phase I reactions (termed "oxidation" even if non oxidative)
- Aliphatic oxidation
- Aromatic hydroxylation
- N-Dealkylation
- O-Dealkylation
- S-Dealkylation
- Epoxidation
- Oxidative deamination
- Sulfoxide formation
- Desulfuration
- N-Oxidation and N-hydroxylation
- Dehalogenation

Front 6

Nonmicrosomal phase I reactions

Back 6

- Alcohol and Aldehyde oxidation
- purine oxidation
- Oxidative deamination (monoamine oxidase and diamine oxidase)

Front 7

Phase I reductions

Back 7

- Azo and nitro reduction

Front 8

Phase I Hydrolysis

Back 8

- Ester and amide hydrolysis
- peptide bond hydrolysis
- Epoxide hydration

Front 9

Phase II reactions (conjugations)

Back 9

- Glucuronidation
- Acetylation
- Mercapturic acid formation
- sulfate conjugation
- N-, O-, and S-methylation
- Trans-sulfuration

Front 10

Three functional groups of human P450 enzymes

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- metabolism of foreign chemicals
- adrenal and gonadal steroidogenesis
- other endogenous functions

Front 11

CYP3A4

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- CYP3A 28% total hepatic P450 content
- isoform 4 thought to be responsible for intestinal presystemic elimination of many drugs with low bioavailability

Front 12

CYP2D6

Back 12

- 4% of total hepatic P450 content
- oxidative metabolism of beta-adrenergic antagonists
- demethylation of tricyclic antidepressants
- demethylation of codeine to morphine
- 5-10% Caucasians have deficient phenotype; autosomal recessive; insensitive to codeine due to inability to demethylate

Front 13

CYP2E1

Back 13

- labile isoform induced in chronic alcoholism

Front 14

CYP1A2

Back 14

- 12% of hepatic P450 content
- metabolism of theophylline
- induced by flavonoids and polycyclic aromatic hydrocarbons

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Seven steps of P450 cycle

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1. Oxidised (Fe3+) cytochrome forms cytochrome P450/drug complex
2. reductase/NADPH system reduces complex to Fe2+ (adds an electron)
3. interaction with molecular oxygen to form cytochrome P450 (Fe2+)/O2/drug complex
4. complex reduced by reductase/NADPH, accepts a hydrogen atom -> cytochrome P450 (Fe3+)/peroxide anion/drug complex
5. accepts proton to give water, P450 ferric oxene/drug complex
6. Ferric oxene extracts H from drug-H to form free radicals (drug radical and hydroxide radical)
7. drug radical and hydroxide radical unite, drug is hydroxylated, cytochrome P450 regenerated.

Front 16

Cytochrome P450 independent oxidations

Back 16

- Amine oxidases (flavin-containing monooxygenase, FMO), metabolizes phenylethylamine and epinephrine
- dehydrogenations (Alcohol dehydrogenase)
- xanthine oxidase

Front 17

Glucuronidation

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- Endogenous reactant is UDP glucuronic acid
- Transferase is UDP-glucuronyl transferase in microsomes
- Types of stbstrates are phenols, alcohols, carboxylic acids, hydroxylamines, sulfonamides
- examples; nitrophenol, morphine, acetaminophene, diazepam, N-hydroxydapsone, sulfathiazole, meprobamate, digitoxin, digoxin