A factor that is likely to increase the duration of action of a drug that is partially metabolized by CYP3A4 in the liver is:

Chronic administration of cimetidine with the drug

Chronic administration of phenobarbital with the drug

Displacement from tissue binding sites by another drug

Chronic administration of rifampicin

Bile salts undergo conjugation for enhanced solubility:

After conjugation with taurine and glycine

After conjugation with derived proteins

After conjugation with betaglucuronic acid

All of the following are true about glutathione, except:

It converts hemoglobin to methemoglobin

It is co-factor of various enzymes

Alcohol is metabolized by all the following pathways except?

MEOS (Microsomal Ethanol Oxidizing System)

Drug Metabolism for FMGE: High-Yield Biochemistry Lessons

Drug Metabolism Basics & Phase I - Kickstarting Cleanup

Drug metabolism (biotransformation) converts lipophilic drugs into more polar, hydrophilic metabolites for easier excretion.

Primary Site: Liver (microsomes in SER). Others: GIT, lungs, kidney.
Phases:
- Phase I: Functionalization (introduce/unmask polar group).
- Phase II: Conjugation (add endogenous substrate).

Phase I Reactions: "Kickstart" drug inactivation & excretion.

Types: Oxidation, Reduction, Hydrolysis (📌 Mnemonic: OHR).
Cytochrome P450 (CYP450) System:
- Major enzyme family for Phase I. Located in hepatic SER.
- Requires: NADPH, $O_2$.
- Mechanism: Drug + $O_2$ + $NADPH + H^+$ $\rightarrow$ Drug-OH + $H_2O$ + $NADP^+$.
- Key Isoforms: CYP3A4, CYP2D6, CYP2C9, CYP2C19, CYP1A2.
  - CYP3A4 metabolizes ~50% of drugs.
Other Enzymes: Alcohol/aldehyde dehydrogenases, esterases, amidases, Flavin-containing monooxygenases (FMOs).

⭐ CYP3A4, the most abundant hepatic isoform, metabolizes ~50% of clinical drugs, highlighting its critical role.

Phase II Reactions - Tag & Toss Conjugation

Purpose: Significantly increases water solubility of xenobiotics, reduces pharmacological activity, and facilitates their renal or biliary excretion. Mechanism: Involves covalent attachment (conjugation) of an endogenous polar molecule to a functional group on the drug or its Phase I metabolite.

Reaction	Enzyme(s)	Endogenous Substrate	Key Points
Glucuronidation	UGT	UDPGA	Most common. Morphine, Paracetamol (major). Bilirubin.
Sulfation	SULT	PAPS	Phenols, alcohols. Paracetamol (minor). Steroids.
Acetylation	NAT (NAT1, NAT2)	Acetyl-CoA	Isoniazid, Hydralazine, Sulfonamides. 📌 Genetic polymorphism (slow/fast acetylators).
Amino Acid Conj.	N-Acyltransferase	Glycine, Glutamine	Carboxylic acids (e.g., Salicylates, Benzoic acid).
Glutathione Conj.	GST	GSH	Detoxifies reactive electrophiles, epoxides. NAPQI (paracetamol toxic metabolite).
Methylation	TPMT, COMT	SAM	Minor role for drugs. Catechols, Thiopurines (e.g., Azathioprine - TPMT polymorphism).

Factors & Clinical Relevance - Modulators & Mayhem

Genetic Factors:
- Pharmacogenomics: Gene variations (e.g., CYP2D6, NAT2) alter drug response.
- Slow/fast acetylators (NAT2); poor/ultrarapid metabolizers (CYP2D6).
Physiological Factors:
- Age: Neonates & elderly ↓ metabolism.
- Disease: Liver/kidney disease ↓ metabolism.
- Pregnancy: Variable effects.
Environmental Factors:
- Diet: Grapefruit juice ↓ CYP3A4.
- Smoking: ↑ CYP1A2 (e.g., theophylline).
- Alcohol: Acute ↓, chronic ↑ metabolism.
Drug Interactions (DDIs):
- Enzyme Induction: ↑ metabolism, ↓ drug efficacy or ↑ toxic metabolite.
  - Inducers: Rifampicin, Phenytoin, Carbamazepine, Barbiturates, St. John's Wort. 📌 CRAP GPS.
- Enzyme Inhibition: ↓ metabolism, ↑ drug efficacy or ↑ toxicity.
  - Inhibitors: Cimetidine, Ketoconazole, Erythromycin, Grapefruit juice. 📌 SICKFACES.COM.
Clinical Significance:
- Adverse Drug Reactions (ADRs), DDIs, therapeutic failure.
- Dose individualization, Therapeutic Drug Monitoring (TDM).

⭐ Warfarin dose adjustments based on CYP2C9 & VKORC1 genotypes are crucial to prevent bleeding/clotting.

Drug metabolism enzyme induction and inhibition

High‑Yield Points - ⚡ Biggest Takeaways

Phase I reactions (oxidation, reduction, hydrolysis) increase drug polarity, mainly via Cytochrome P450 (CYP450).

CYP450 inducers (e.g., rifampicin, phenobarbital) ↓ drug effect; inhibitors (e.g., ketoconazole, erythromycin) ↑ toxicity.

Phase II reactions (conjugation: glucuronidation, sulfation) make drugs water-soluble for excretion.

Glucuronidation is key in Phase II; deficient in Gilbert's & Crigler-Najjar syndromes.

Slow acetylators (genetic variation) risk ↑ toxicity from drugs like isoniazid.

Grapefruit juice inhibits CYP3A4, significantly ↑ drug bioavailability_._

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Drug Metabolism