Pharmacokinetics

Fundamental Pharmacokinetic Principles

ADME Overview

• Pharmacokinetics describes what the body does to a drug, encompassing four key processes:
• Absorption: How the compound enters systemic circulation
• Distribution: How it spreads throughout body tissues
• Metabolism: How it’s chemically modified
• Excretion: How it’s eliminated from the body

Pharmacokinetic Parameters

Key Metrics

Integration of quality throughout manufacturing:

• Bioavailability (F): Fraction reaching systemic circulation
• Half-life (t½): Time for plasma concentration to reduce by 50%
• Clearance (CL): Volume of plasma cleared per unit time
• Volume of distribution (Vd): Apparent volume in which drug distributes

Absorption Characteristics

Oral Bioavailability

Gastrointestinal Absorption

Most SARMs demonstrate excellent oral bioavailability due to:

• Optimal lipophilicity for membrane permeation
• Resistance to gastric acid degradation
• Efficient transport across intestinal epithelium

Comparative Bioavailability

Key considerations for SARM analysis:

• Ostarine (MK-2866): ~90% bioavailability
• Ligandrol (LGD-4033): ~95% bioavailability
• RAD140: ~85-90% bioavailability
• MK677: >90% bioavailability

Factors Affecting Absorption

Food Effects

Studies indicate minimal food effects on SARM absorption:

• High-fat meals may slightly delay absorption
• Overall bioavailability remains largely unaffected
• Clinical recommendation: consistent timing regardless of meals

pH Stability

SARMs demonstrate excellent stability across physiological pH ranges:

• Stable in gastric acid conditions (pH 1-3)
• Maintained integrity in intestinal environments (pH 6-8)
• No significant degradation during transit

Distribution Properties

Tissue Distribution

Target Tissue Accumulation

SARMs preferentially accumulate in target tissues:

• Skeletal muscle: 2-4x higher concentrations than plasma
• Bone tissue: 3-5x higher concentrations than plasma
• Adipose tissue: Lower accumulation relative to muscle

Blood-Brain Barrier Penetration

Varying degrees of CNS penetration:

• RAD140: Demonstrates significant brain penetration
• Ostarine: Limited CNS access
• LGD-4033: Moderate brain tissue distribution

Protein Binding

Plasma Protein Interactions

High protein binding observed across SARM classes:

• Albumin binding: Primary binding protein (85-95%)
• Alpha-1-acid glycoprotein: Secondary binding (5-15%)
• Free fraction: Typically 2-8% of total plasma concentration

Clinical Implications

High protein binding affects:

• Duration of action (longer half-lives)
• Drug-drug interactions with highly bound compounds
• Tissue distribution patterns

Metabolic Pathways

Phase I Metabolism

Cytochrome P450 Systems

Primary metabolic enzymes involved:

• CYP3A4: Major metabolic pathway for most SARMs
• CYP2C9: Secondary pathway for some compounds
• CYP2D6: Minor contributions to metabolism

Metabolic Reactions

Common Phase I transformations:

• Hydroxylation at various positions
• N-dealkylation reactions
• Oxidative deamination
• Epoxide formation (rare)

Phase II Metabolism

Conjugation Reactions

Secondary metabolic processes:

• Glucuronidation: Primary conjugation pathway
• Sulfation: Secondary conjugation mechanism
• Methylation: Minor pathway for some SARMs

Metabolite Profiles

Typical metabolite patterns:

• Hydroxylated metabolites: 40-60% of dose
• Glucuronide conjugates: 20-30% of dose
• Sulfate conjugates: 10-15% of dose
• Unchanged parent compound: 5-15% of dose

Compound-Specific Pharmacokinetics

Ostarine (MK-2866)

Pharmacokinetic Profile

• Half-life: 24 hours
• Time to peak (Tmax): 1-2 hours
• Clearance: 15-20 L/hr
• Volume of distribution: 400-500 L

Metabolic Characteristics

• Primary metabolism via CYP3A4
• Major metabolite: 4-hydroxylated derivative
• Extensive glucuronidation of metabolites
• Renal elimination: 65% of dose

Ligandrol (LGD-4033)

Pharmacokinetic Profile

• Half-life: 24-36 hours
• Time to peak (Tmax): 1-3 hours
• Clearance: 10-15 L/hr
• Volume of distribution: 500-700 L

Metabolic Characteristics

• Slower metabolism than other SARMs
• Extensive protein binding (>95%)
• Multiple hydroxylated metabolites
• Predominantly hepatic elimination

RAD140 (Testolone)

Pharmacokinetic Profile

For solution characterization:

• Half-life: 16-20 hours
• Time to peak (Tmax): 2-4 hours
• Clearance: 20-25 L/hr
• Volume of distribution: 300-400 L

Metabolic Characteristics

For solution characterization:

• More rapid metabolism than other SARMs
• Significant first-pass metabolism
• Brain tissue accumulation notable
• Mixed hepatic and renal elimination

MK677 (Ibutamoren)

Pharmacokinetic Profile

• Half-life: 24-30 hours
• Time to peak (Tmax): 2-3 hours
• Clearance: 5-8 L/hr
• Volume of distribution: 200-300 L

Metabolic Characteristics

• Slower clearance than traditional SARMs
• High plasma protein binding (98%)
• Extensive hepatic metabolism
• Long duration of pharmacological effect

Excretion Pathways

Renal Elimination

Urine Composition

Typical urinary elimination patterns:

• Glucuronide conjugates: 40-50% of dose
• Hydroxylated metabolites: 15-25% of dose
• Sulfate conjugates: 10-15% of dose
• Unchanged parent: 5-10% of dose

Renal Clearance

• Active tubular secretion: Limited contribution
• Passive filtration: Primary mechanism
• Tubular reabsorption: Significant for some metabolites

Hepatic Elimination

Biliary Excretion

• Molecular weight threshold: >500 Da favors biliary excretion
• Some SARMs undergo enterohepatic recirculation
• Contributes to extended half-lives

Fecal Elimination

• Direct biliary excretion: 20-35% of dose
• Unabsorbed oral dose: 5-10% of dose
• Bacterial metabolism in colon: Minor contribution

Factors Affecting Pharmacokinetics

Individual Variability

Genetic Polymorphisms

CYP enzyme variants affecting metabolism:

• CYP3A4*1B: Reduced metabolic activity
• CYP2C9 variants: Altered clearance patterns
• UGT enzyme polymorphisms: Variable conjugation rates

Age-Related Changes

Pharmacokinetic alterations with aging:

• Reduced hepatic metabolism (20-30% decrease)
• Decreased renal clearance (40-50% reduction)
• Altered body composition affecting distribution

Disease States

Hepatic Impairment

Effects on SARM pharmacokinetics:

• Reduced clearance and extended half-lives
• Increased bioavailability due to reduced first-pass metabolism
• Altered protein binding in severe liver disease

Renal Impairment

Impact on elimination:

• Reduced clearance of metabolites
• Potential accumulation of active compounds
• May require dose adjustments in severe impairment

Drug-Drug Interactions

CYP3A4 Interactions

Enzyme Inhibitors

Compounds that may increase SARM exposure:

• Ketoconazole: Strong CYP3A4 inhibitor
• Grapefruit juice: Moderate inhibitor
• Clarithromycin: Strong inhibitor

Enzyme Inducers

Compounds that may reduce SARM exposure:

• Rifampin: Strong CYP3A4 inducer
• St. John’s Wort: Moderate inducer
• Carbamazepine: Strong inducer

Transporter Interactions

P-glycoprotein

Some SARMs interact with efflux transporters:

• May affect absorption and distribution
• Potential for drug-drug interactions
• Clinical significance generally limited

Analytical Considerations

Detection Methods

Mass Spectrometry

Gold standard for SARM analysis:

• LC-MS/MS: High sensitivity and specificity
• HRMS: Accurate mass determination
• Detection limits: ng/mL to pg/mL ranges

Sample Preparation

Common extraction methods:

• Protein precipitation: Simple and rapid
• Liquid-liquid extraction: Clean extracts
• Solid-phase extraction: High recovery rates

Stability Considerations

Sample Stability

Storage requirements for accurate analysis:

• Frozen plasma: Stable for 6-12 months
• Room temperature: Stable for 4-8 hours
• Repeated freeze-thaw: Minimal degradation (3 cycles)

Clinical Implications

Dosing Optimization

Pharmacokinetic-Based Dosing

Half-life considerations for dosing frequency:

• Long half-life compounds (>20 hours): Once daily dosing
• Medium half-life (12-20 hours): Once to twice daily
• Short half-life (<12 hours): Multiple daily doses

Steady-State Considerations

Time to reach steady-state:

• 5 half-lives for 97% of steady-state
• Ostarine: 5 days to steady-state
• Ligandrol: 7-8 days to steady-state
• RAD140: 4-5 days to steady-state

Monitoring Parameters

Therapeutic Drug Monitoring

While not routinely performed, TDM may be useful for:

• Ensuring adequate exposure
• Monitoring compliance
• Adjusting doses in special populations

Future Directions

Pharmacokinetic Modeling

Population PK Models

Development of models incorporating:

• Demographic covariates
• Disease state effects
• Genetic polymorphism influences

PBPK Modeling

Physiologically-based models for:

• Predicting tissue concentrations
• Scaling from preclinical to clinical
• Drug-drug interaction predictions

Novel Formulations

Modified Release Systems

Development of formulations for:

• Extended release profiles
• Targeted tissue delivery
• Improved bioavailability

Conclusion

Understanding SARM pharmacokinetics is essential for optimizing therapeutic outcomes and minimizing adverse effects. The generally favorable ADME properties of SARMs, including high oral bioavailability and predictable elimination patterns, contribute to their clinical utility.

Continued research into individual pharmacokinetic variability, drug interactions, and optimization strategies will further enhance our ability to use these compounds effectively and safely. The application of modern pharmacokinetic modeling and simulation techniques promises to accelerate development and improve therapeutic applications of current and future SARMs.