ADME & Pharmacokinetics
Understanding how drugs move through your body—and why testing in human-relevant systems is essential for predicting real-world drug behavior
What is ADME?
The four processes that determine a drug's journey through your body
Absorption
How the drug enters your bloodstream. For oral drugs, this happens primarily in the small intestine. The drug must cross cell membranes and survive first-pass metabolism.
Distribution
How the drug spreads throughout your body. Factors like blood flow, tissue binding, and the blood-brain barrier determine where the drug can reach and accumulate.
Excretion
How your body eliminates the drug. The kidneys filter drugs from blood into urine, while the liver excretes some drugs via bile into feces. This determines how long the drug stays active.
The CYP450 Family
These liver enzymes metabolize ~75% of all drugs—and vary dramatically between species
Why Animal ADME Data Fails
Species-specific differences make animal pharmacokinetics unreliable predictors of human response
Human ADME
- ✓ CYP2D6 metabolizes 25% of drugs—single gene form
- ✓ CYP3A4 is the dominant drug-metabolizing enzyme
- ✓ Specific UGT enzymes for glucuronidation
- ✓ P-gp transporter with human-specific substrates
- ✓ Albumin binding with human-specific affinity
- ✓ Renal clearance based on human GFR (~120 mL/min)
- ✓ Bile acid composition affects enterohepatic cycling
Animal ADME
- ✗ CYP2D6 doesn't exist in mice—rats have 6 forms
- ✗ Different CYP3A isoforms with altered specificity
- ✗ Different Phase II enzyme expression patterns
- ✗ Transporter substrates vary by species
- ✗ Plasma protein binding differs significantly
- ✗ Allometric scaling often fails for clearance
- ✗ Different bile composition affects absorption
Understanding Bioavailability
The fraction of drug that reaches systemic circulation unchanged
Example: A drug with 70% gut absorption and 40% survival through first-pass metabolism has 28% oral bioavailability (F = 0.70 × 0.40 = 0.28)
How NAMs Improve ADME Predictions
Human-relevant models provide accurate pharmacokinetic data
Gut-on-Chip
Human intestinal cells with villi structures predict oral absorption, P-gp efflux, and drug-food interactions accurately.
Liver-on-Chip
Primary human hepatocytes with correct CYP450 expression predict metabolism, clearance, and drug-drug interactions.
Kidney-on-Chip
Proximal tubule cells under flow predict renal clearance, transporter-mediated secretion, and nephrotoxicity.
BBB-on-Chip
Blood-brain barrier models predict CNS drug penetration—critical for neurological drugs and avoiding neurotoxicity.
Multi-Organ Systems
Connected organ chips model complete ADME—absorption in gut, metabolism in liver, excretion via kidney—in one system.
PBPK Modeling
AI-powered physiologically-based pharmacokinetic models integrate human data to predict concentration-time profiles.
Key Pharmacokinetic Terms
Essential vocabulary for understanding ADME
Bioavailability (F)
Fraction of administered dose that reaches systemic circulation. IV drugs have F=1 (100%); oral drugs typically F=0.1-0.9.
Half-life (t½)
Time for plasma drug concentration to decrease by 50%. Determines dosing frequency—drugs with short t½ need more frequent dosing.
Clearance (CL)
Volume of plasma cleared of drug per unit time (mL/min). Total clearance = hepatic + renal + other elimination routes.
Volume of Distribution (Vd)
Theoretical volume needed to contain total drug at plasma concentration. High Vd means extensive tissue distribution.
First-Pass Metabolism
Drug metabolism in gut wall and liver before reaching systemic circulation. Can dramatically reduce oral bioavailability.
AUC (Area Under Curve)
Total drug exposure over time, calculated from concentration-time curve. Key metric for bioequivalence studies.
Cmax
Maximum plasma concentration achieved after dosing. Important for efficacy (must reach therapeutic level) and safety (must not exceed toxic level).
Tmax
Time to reach maximum concentration. Reflects absorption rate—faster absorption = earlier Tmax.