4.3 Physicochemical Properties, ADME, and Drug Metabolism Pathways
Key Takeaways
- Lipinski's Rule of Five (MW <= 500, logP <= 5, H-bond donors <= 5, H-bond acceptors <= 10) predicts oral drug-likeness for passively absorbed molecules.
- Henderson-Hasselbalch governs ionization: weak acids are unionized (and absorbed) in the stomach, weak bases are unionized (and absorbed) in the intestine.
- logP measures lipophilicity of the unionized form; logD at pH 7.4 better predicts in vivo distribution because it accounts for ionization.
- Phase I metabolism (mainly CYP450) introduces or unmasks polar groups via oxidation, reduction, or hydrolysis; CYP3A4 metabolizes about half of all drugs.
- Phase II metabolism conjugates a polar endogenous group (glucuronide, sulfate, acetate, glutathione, methyl, or amino acid) to produce water-soluble metabolites for excretion.
4.3 Physicochemical Properties, ADME, and Drug Metabolism Pathways
Quick Answer: A drug's physicochemical signature (molecular weight, lipophilicity, ionization, solubility, protein binding) dictates its ADME fate. The CYP450 enzyme family drives Phase I oxidation; conjugation reactions drive Phase II. Master these to predict bioavailability, drug interactions, and patient variability.
Medicinal chemistry explains why a molecule behaves in the body the way it does. The FPGEE frequently tests physicochemical relationships and metabolism pathways because they form the mechanistic basis for pharmacokinetics, drug interactions, and individual variability.
Lipinski's Rule of Five
Pfizer's Christopher Lipinski proposed a heuristic for drug-likeness - the likelihood that a small molecule is orally bioavailable via passive absorption:
| Parameter | Threshold |
|---|---|
| Molecular weight | <= 500 Da |
| logP (lipophilicity) | <= 5 |
| H-bond donors | <= 5 |
| H-bond acceptors | <= 10 |
Two or more violations suggest poor oral absorption. The rule applies only to passively absorbed molecules; substrates of active transporters (e.g., some antibiotics, oncologics, peptides) routinely violate it and still absorb well.
Ionization and Absorption
The Henderson-Hasselbalch equation governs the unionized fraction that crosses lipid membranes by passive diffusion. Unionized drug is lipophilic and crosses; ionized drug is hydrophilic and remains in the lumen.
| Drug type | Predominant site of absorption | Why |
|---|---|---|
| Weak acid (pKa 3 to 5) | Stomach (pH 1 to 3) | Mostly unionized at low pH |
| Weak base (pKa 8 to 10) | Intestine (pH 5 to 7) | Mostly unionized at higher pH |
Very weak acids (pKa > 7) or very weak bases (pKa < 5) are largely unionized throughout the GI tract and are absorbed everywhere.
Lipophilicity: logP and logD
- logP = partition coefficient (octanol/water) for the unionized form of a molecule.
- logD = distribution coefficient at a stated pH, accounting for ionization.
The optimal logP for oral drugs is typically 1 to 3. Higher logP increases membrane permeability but reduces aqueous solubility, raises metabolism, and increases protein binding. Lower logP impairs permeability. logD at pH 7.4 is the best single predictor of in vivo distribution behavior.
Solubility and Solid-State Properties
- Polymorphism: the same molecule can crystallize in different packing arrangements. Polymorphs differ in solubility, dissolution rate, and bioavailability - the classic case is the ritonavir polymorph II crisis of 1998, which forced a market withdrawal.
- Amorphous vs crystalline: amorphous forms have higher free energy, dissolve faster, but are physically less stable.
- Hydrates: water molecules occupy specific positions in the crystal lattice; hydrates are usually less soluble than the corresponding anhydrate.
- Cosolvents: ethanol, propylene glycol, glycerin, and polyethylene glycol increase the solubility of poorly water-soluble drugs in parenteral formulations.
Protein Binding
| Protein | Binds | Clinical effect |
|---|---|---|
| Albumin | Acidic and neutral drugs | High binding means low free fraction; displacement raises free drug |
| alpha-1-acid glycoprotein (AAG) | Basic drugs | Inflammation raises AAG, increasing binding of basic drugs |
Only free drug is pharmacologically active, distributes into tissues, is metabolized, and is cleared. Total drug concentration assays can mislead in hypoalbuminemia (e.g., phenytoin in ICU patients) because the free fraction rises even when the total concentration looks therapeutic.
ADME Transport Mechanisms
- Passive diffusion: down a concentration gradient; driven by lipophilicity (logD).
- Facilitated or active transport: protein-mediated; saturable; can move against a gradient. Examples: OATP, P-glycoprotein (P-gp), OCT.
- Paracellular transport: between cells; size-limited; minor in GI epithelium.
- Endocytosis: large molecules such as proteins and some biologics.
Drug Metabolism
Metabolism converts lipophilic parent drugs into more polar, excretable metabolites. Two phases are conventionally distinguished.
Phase I - Functionalization
Reactions: oxidation, reduction, hydrolysis. Phase I introduces or unmasks a polar group (OH, NH2, SH, COOH) on the molecule. The reactions are primarily catalyzed by cytochrome P450 (CYP450) enzymes in the hepatic endoplasmic reticulum.
| CYP Enzyme | Share of drugs | Representative substrates | Strong inhibitors | Strong inducers |
|---|---|---|---|---|
| CYP3A4 | ~50% | Midazolam, simvastatin, cyclosporine, many HIV ARVs | Ketoconazole, clarithromycin, ritonavir, grapefruit | Rifampin, carbamazepine, phenytoin, St. John's wort |
| CYP2D6 | ~25% | Codeine, metoprolol, fluoxetine, tamoxifen | Fluoxetine, paroxetine, bupropion, quinidine | None clinically significant |
| CYP2C9 | ~10% | Warfarin (S-enantiomer), NSAIDs, phenytoin, losartan | Fluconazole, amiodarone, sulfamethoxazole | Rifampin, carbamazepine |
| CYP1A2 | ~5% | Theophylline, caffeine, clozapine, tizanidine | Ciprofloxacin, fluvoxamine, oral contraceptives | Tobacco (PAHs), charbroiled meat, omeprazole |
| CYP2C19 | ~5% | Omeprazole, clopidogrel, diazepam | Fluvoxamine, fluconazole, omeprazole | Rifampin, carbamazepine |
Phase II - Conjugation
Phase II attaches a polar endogenous group to the parent drug or Phase I metabolite: glucuronidation, sulfation, acetylation, glutathione conjugation, methylation, amino acid conjugation. Most Phase II metabolites are inactive and water-soluble, but notable exceptions include morphine-6-glucuronide (more active than morphine at the mu receptor) and N-acetylprocainamide (antiarrhythmic activity).
| Reaction | Enzyme system | Example |
|---|---|---|
| Glucuronidation | UGT (liver) | Morphine to morphine-3-glucuronide and morphine-6-glucuronide |
| Sulfation | SULT | Steroids, acetaminophen |
| Acetylation | NAT1 and NAT2 | Isoniazid, hydralazine, procainamide |
| Glutathione conjugation | GST | Acetaminophen detoxification to mercapturic acid |
| Methylation | COMT, TPMT | Catecholamines, 6-mercaptopurine |
Metabolic Variations
- Enzyme induction: increased enzyme synthesis speeds metabolism, lowers drug levels, and reduces effect. Classic inducers: rifampin, phenytoin, carbamazepine, St. John's wort, chronic alcohol, smoking (CYP1A2).
- Enzyme inhibition: competitive or mechanism-based inhibition slows metabolism and raises drug levels. Classic inhibitors: ketoconazole, ritonavir, erythromycin, clarithromycin, grapefruit juice, fluoxetine, ciprofloxacin, amiodarone.
- Genetic polymorphisms matter clinically:
- CYP2D6 poor metabolizers (5 to 10% of Caucasians) get no analgesia from codeine (cannot O-demethylate to morphine); ultra-rapid metabolizers risk fatal overdose from a normal codeine dose.
- CYP2C19 poor metabolizers do not activate clopidogrel effectively, raising stent thrombosis risk; the FDA boxed warning addresses this.
- NAT2 slow acetylators accumulate isoniazid, raising hepatotoxicity and lupus risk.
- TPMT deficiency causes fatal myelosuppression from 6-mercaptopurine and 6-thioguanine; genotype before dosing.
- First-pass effect: metabolism before the drug reaches systemic circulation, occurring in the gut wall, the liver (portal circulation), and (to a small extent) the lung. Sublingual, rectal (lower colon), and parenteral routes bypass hepatic first-pass metabolism.
Clinical Relevance on the FPGEE
The exam expects you to predict clinical consequences from physicochemical and metabolic facts:
- Ketoconazole plus simvastatin raises simvastatin AUC roughly 20-fold via CYP3A4 inhibition, dramatically increasing rhabdomyolysis risk.
- Rifampin plus oral contraceptives causes contraceptive failure via CYP3A4 induction (and possibly via P-gp induction).
- Codeine in a CYP2D6 ultra-rapid metabolizer who is breastfeeding can cause fatal infant morphine exposure (FDA boxed warning).
- Phenytoin in hypoalbuminemia has a higher free fraction at the same total concentration; the therapeutic range based on total concentration does not apply.
Mastering this section gives you the mechanistic framework for the entire pharmacology chapter that follows: drug interactions, adverse effects, and individualized dosing all flow from these physicochemical and metabolic principles.
Which CYP enzyme metabolizes the largest share of clinically used drugs and is strongly inhibited by ketoconazole and grapefruit juice?
A patient on long-term warfarin begins rifampin therapy for tuberculosis. What is the expected effect on warfarin anticoagulation and the underlying mechanism?