Biopharmaceutics and Pharmacokinetics

• Biopharmaceutics studies the relationship between a drug's physicochemical properties and its behavior in the body, essentially combining pharmacokinetics with dosage form considerations.
• Pharmacokinetics (PK) describes drug absorption, distribution, metabolism, and excretion (ADME), also known as input, transfer, and elimination (ITE).

Drug Absorption

• The process of a drug moving from the administration site into the bloodstream.
• Bioavailability (F) represents the fraction of the administered drug that reaches systemic circulation.
• Absorption mechanisms: passive diffusion, facilitated diffusion, paracellular transport, and active transport (requires transporters and ATP).

Factors Affecting Drug Absorption

• Physicochemical properties of the drug.
• Biological and environmental factors at the absorption site.

Drug Distribution

• The reversible transfer of a drug between locations within the body.
• After entering systemic circulation, a drug distributes into interstitial and intracellular fluids.

Volume of Distribution (Vd)

• Vd = (Amount of drug in the body) / (Plasma drug concentration).
• Represents a drug's tendency to stay in the plasma or redistribute to other tissue compartments.
• Example: A 100 mg dose with a plasma concentration of 16 mg/L.

Factors Affecting Drug Distribution

• Organ size and perfusion rate
• Binding of the drug to blood proteins versus tissue
• Tissue permeability.
• Warfarin, highly bound to albumin, has a small Vd (7 L).

Drug Metabolism

• Phase I reactions (oxidation, reduction, hydrolysis, acetylation) followed by Phase II reactions (conjugation, glucuronidation).
• Polar metabolites are excreted in the kidney/urine, while non-polar metabolites undergo fecal excretion.

Goal of Drug Metabolism

• To inactivate the drug and make it more polar for easier elimination by the liver.

Enterohepatic Circulation (EHC)

• Substances move between the liver and small intestine.
• Liver secretes substances into bile → bile enters the small intestine → substances are absorbed into enterocytes → substances are transported back to the liver via the portal vein.

Bile Acids

• Steroid molecules produced in the liver to aid in the absorption of fats and fat-soluble vitamins in the small intestine.
• Emulsify fats and act as signaling molecules through receptors like FXR to regulate metabolic processes.

Contraceptive Failure and Antibiotics

• Antibiotics can disrupt enterohepatic circulation, leading to contraceptive failure.
• Estrogen from birth control pills is reabsorbed after liver metabolism and excretion into the bile.
• Gut bacteria, altered by antibiotics, are needed for reabsorption; disruption can lower hormone levels.
• Rifampicin, an antibiotic, induces liver enzymes and can lower oral contraceptive hormone levels.

Drug Clearance (Cl)

• Volume of fluid cleared of drug from the body per unit of time (mL/min or L/hr).
• Cl = Elimination rate / Concentration.

Compartment Models

• One-compartment model: Drug is injected and immediately distributes throughout the entire body.
• Two-compartment model: Drug distributes to a central compartment first, then to a peripheral compartment.

Central Compartment

• Organs with high blood supply receive the drug quickly (heart, kidney, liver, lungs).

Peripheral Compartment

• Organs with less blood supply take longer for the drug to reach and retain it for a longer time (spine, brain, skin).

AUC (Area Under the Curve)

• Reflects the body's actual exposure to a drug after administration, expressed in mg*h/L.
• Dependent on the rate of drug elimination and the administered dose.

T 1/2 (Half-Life)

• The time it takes for half of the drug concentration to fall during the elimination phase.
• Plasma concentration falls by half in each half-life period.
• Used for determining dosing frequency.

Fraction Bioavailability (F)

• Fraction of the administered drug that reaches the systemic circulation intact.
• Determines the required dosage for each drug via each route of administration.
• F = (AUC oral / AUC IV) x (Dose IV / Dose oral).

Mean Residence Time (MRT)

• The average duration that a drug remains in the body.
• Calculated by dividing the area under the plasma concentration-time curve (AUC) by the total amount of drug administered.

Absorption Rate Constant (Ka)

• Represents how quickly drug absorption occurs, driven by the liver.

Excretion Rate Constant (Ke)

• Represents how quickly a drug is excreted, driven by the liver.

Steady State Concentration (Css)

• Occurs when the amount of drug absorbed equals the amount cleared from the body during continuous or repeated dosing; drug concentration remains consistent.

Glomerular Filtration Rate (GFR)

• Measures how quickly the drug is filtered in the kidney, indicating kidney function.
• Standard GFR is approximately 120 mL/min.
• Checked with a serum creatinine test.

Loading Dose

• An initial, higher dose of a drug, followed by a maintenance dose.
• Used to achieve steady-state concentration quickly.
• Slow elimination (high half-life) requires a higher loading dose; fast elimination (low half-life) requires a lower loading dose.

Extraction Ratio (ER)

• Fraction of a drug removed from the blood as it crosses an eliminating organ (liver or kidney).
• Percentage of drug entering the kidney that is excreted into the final urine.
• ER = Cl liver / Q.

Liver Blood Flow (Q)

• Measured in mL/min.

Dosing Interval (t)

• The time between doses.

Drug Concentration Curve

• Phases: onset time → absorption phase (up the curve) → peak (Cmax) → duration of action (curve) → elimination phase (down the curve).

Therapeutic Range

• Minimum Effective Concentration (MEC): The lowest drug concentration needed to achieve a therapeutic benefit.
• Maximum Therapeutic Concentration or Minimum Toxic Concentration (MTC): The concentration at which a drug produces unwanted side effects.
• The therapeutic range lies between the MTC and MEC.

Therapeutic Drug Monitoring

• Clinical practice of measuring specific drug concentrations at intervals to maintain a constant concentration.
• Allows for safer and more rapid achievement of therapeutic drug concentrations compared to empiric dose changes.

Drug Transport into Cells

• Cells have a lipid bilayer composed of phospholipids (hydrophilic head and hydrophobic tail).
• Liposome drugs can pass through the lipid bilayer.

Passive Diffusion

• Drug molecules pass through a membrane without active participation from the membrane.

Fick's First Law

• Describes that the rate of diffusion across a membrane is proportional to the difference in drug concentrations on both sides of the membrane.

Absorption Process

• Driven by the concentration gradient of the drug across the membrane, based on its aqueous solubility and formulation.

Carrier-Mediated Transport

• Primarily for hydrophilic molecules.
• Molecules bind to membrane protein carriers for transport.

Facilitated Diffusion

• A carrier-mediated process occurring only in the presence of a concentration gradient.

Active Transport

• Requires energy (ATP) and a carrier protein.
• Solutes can be transported against the concentration gradient.
• The rate of active transport follows the Michaelis-Menten equation: Rate of drug absorption = C x Vmax / (Km + C).

Action Potential Curve

• Depolarization: Na+ in, Ca2+ in, K+ out.
• Repolarization: K+ out.

Rate-Determining Steps

• Rate of dissolution (rate-limiting for BCS class 2 drugs).
• Rate of drug permeation through the biomembrane (rate-limiting for BCS class 3 drugs).

Lipinski's Rule of 5

• Poor permeation is likely when: molecular weight is greater than 500 Daltons, log P is over 5, more than 5 H-bond donors, or more than 10 H-bond acceptors.

Ionization of Drugs

• Drugs must be un-ionized (no charge) for absorption.
• Rates of dissolution and absorption are related to ionization constants.
• Non-ionized forms of acidic/basic drugs are lipid-soluble and better absorbed.

pH Partition Theory

• Ionized drugs cannot pass through the lipid membrane (due to +/- charge).
• Non-ionized drugs have higher lipid solubility and can pass through the lipid membrane easily.

Particle Size of Drugs

• Influences oral absorption.
• Smaller particle sizes dissolve more rapidly due to increased surface area.
• Exceptions: Tetracycline (already soluble), erythromycin (destroyed in the gut), extended-release drugs.

Polymorphism

• The ability of a substance to crystallize in two or more different crystal forms.
• Same chemical structure but different crystal lattice conformations.

Solubility of Compound Forms

• The amorphous form (no crystal form, random shape) of a compound is always more soluble than its corresponding crystal form.

Partition Coefficient (Oil/Water)

• Measures drug lipophilicity.
• P o/w = (C oil / C water) at equilibrium.
• Partition (P) or distribution (D) coefficient is the ratio of a compound's concentration in two phases of a mixture.
• An increased log P indicates increased permeability.

Log P

• The log of the ratio of concentrations of the un-ionized solute in solvents.
• When P is greater than 1: lipophilic drug.
• When P is less than 1: hydrophilic drug.

Biopharmaceutical Classification System (BCS)

• Class I: High solubility and permeability.
• Class II: Low solubility and high permeability.
• Class III: High solubility and low permeability.
• Class IV: Low solubility and permeability.
• The more polar a drug is, the less permeable it is.

High Solubility

• A drug is highly soluble when the highest dosage strength is soluble in 250 mL or less of aqueous media over the pH range of 1-7.5.

High Permeability

• A drug is highly permeable if the absorption of an orally administered dose in humans is over 90%.

Disintegration Time

• How long it takes for a tablet to break down into powder.
• Tablets have the slowest absorption time; solutions have the fastest.

Physiological Factors Affecting Absorption

• Area of absorptive surface.
• Vascularity: More vascularity = extensive absorption; vasoconstriction = less absorption.
• pH and pKa.
• GI emptying process and motility.
• Functional integrity of the surface (e.g., burns increase skin permeability).
• Diseases.
• First-pass metabolism.

Ideal Log P for Transdermal Patch

• A log P of 1-3 is best for permeating the skin, making it ideal for transdermal drug patches.

Occlusion

• Prevents water from escaping skin, and the presence of water in the skin allows increased drug permeability.
• Use oily ointments like Aquaphor to increase skin moisture and drug permeability.

Role of FcRn

• A protein that helps maintain the levels of IgG and albumin in the blood.
• FcRn (neonatal Fc receptor) facilitates the transcytosis of IgG across epithelial barriers, allowing for targeted delivery of therapeutic proteins to specific tissues.
• Binds to the Fc region of IgG, acting as a "molecular shuttle" for drug delivery across mucosal membranes.

Exercise and Heat Effects

• Alter blood flow distribution within the body.
• Drugs in areas with increased blood flow during exercise (muscles) will be absorbed faster; absorption in areas with decreased blood flow will be slowed.
• Heat exposure can enhance the absorption of transdermal drugs.

Oral Route of Administration

• Most natural, uncomplicated, and pain-free route.
• Stomach = dissolution of the drug.
• Small intestine = absorption of the drug.
• Colon = fermentation of the drug.

SubQ and IM Administration

• Drugs given subQ and IM if drugs are unstable in the GI tract or are degraded by digestive enzymes.
• Insulin can potentially be given via oral, transdermal, pulmonary, subQ, or IM routes.

Drug in Stomach

• Minimal drug absorption from the stomach.
• Drugs stay in the stomach for 10 minutes to 2 hours.
• The stomach grinds solid dosage forms and releases the drug.
• Drugs are broken down in gastric fluid with a pH range of 1-3.

Small Intestine

• The most important region for oral drug absorption.
• Large surface area and long residence time (4 hours) are optimal for absorption.
• Epithelial cell surface with microvilli (brush border).

Drug in Colon

• No drug absorption.
• Unabsorbed drug that reaches the colon is excreted in feces.

Buffering Systems

• Gastric pH is highly acidic in the fasting state.
• After a meal, gastric pH becomes more alkaline due to the buffering effect of food.
• The alkaline environment of the small intestine remains relatively consistent.

Gastric Emptying Time

• The time a drug will stay in the stomach before it is emptied into the small intestine.
• Controlled by esophageal and pyloric sphincters.

Migrating Motor Complex (MMC)

• Peristalsis in the small intestine moves the last remnants of a drug, bacteria, and debris into the large intestine.
• Increased motility = not enough time for drug absorption.

Factors Affecting Gastric Emptying and Intestinal Motility

• Amount of food.
• Caloric content (delays gastric emptying).
• Temperature (hot meals).
• High viscosity (reduces diffusion).
• Physical form of food.
• Acidic content (an increase in acidic content decreases the emptying rate).
• Age, hormones, and posture.

First-Pass Metabolism

• Absorbed drug is transported via the mesenteric vessels to the hepatic portal vein and then to the liver before entering systemic circulation.
• Drugs that are highly metabolized by the liver have poor systemic availability.

Negative Food Effect

• A drug has a negative food effect if the co-administration of food decreases its area under the curve (AUC) compared to administration on a fasted stomach.
• Reduced Cmax = reduced oral bioavailability.

Lipid-Soluble Drugs

• Better absorbed with high-fat content foods.

Chelation of Drugs

• Binding of drugs to calcium, iron, or magnesium reduces the absorption of fluoroquinolones, tetracyclines, and cephalosporins.
• Calcium reduces drug absorption.

Microbiota

• Healthy bacteria in the gut break down bile from the liver.
• Antibiotics affect the microbiota, therefore affecting bile breakdown.
• Microbiota affect the absorption and metabolism of drugs.

Acidic Drug in Acidic Beverage

• Weakly acidic drugs, like ibuprofen, taken with acidic Coca-Cola can increase drug exposure.
• Acidic drugs are absorbed better in acidic environments because they become un-ionized.
• Cmax and AUC of ibuprofen increase w Coca Cola, dose of ibuprofen must be reduced when giving w Coke

Basic Drug in Acidic Beverage

• Basic drugs like ketoconazole and itraconazole can be absorbed better when taken with acidic beverages like Coca-Cola.
• Acidic beverages can increase the solubility of these drugs.

Enzymes in Small Intestine

• P-glycoprotein and cytochrome P450 3A4 work synergistically to reduce the bioavailability of drugs (reduce oral absorption).

Effect of Cranberry Juice

• Inhibits the activity of CYP2C9, the enzyme responsible for the metabolism of warfarin.

Effect of Broccoli/Brussel Sprouts/Spinach

• Cruciferous vegetables induce the activity of enzymes in the liver that break down medications, potentially decreasing the effectiveness of some drugs if consumed in large quantities.
• Contain glucosinolates that induce enzymes involved in drug metabolism, particularly CYP1A2 and GST, that can lead to faster breakdown of certain medications, lowering their therapeutic levels.

Amiodarone and Grapefruit Juice

• CYP3A4 interaction leads to QT prolongation and ventricular arrhythmia.

Formulation Influence on Food Effects

• Liquids empty faster than solids.
• Dimension of food particles.
• Size limit of 1.8-2.2 mm for particles to pass through the pyloric sphincter.
• Liquid medicines given with food may have delayed transit to the small intestine.

Patterns of Distribution

• Largely confined to the vascular system (stays in the blood).
• Throughout the body water (distributes in intravascular to interstitial spaces with water for hydrophilic drugs).
• Concentrated specifically in one tissue/gland/organ.
• Non-uniform distribution (most drugs).

Volume of Distribution

• The volume of sampled fluid needed to account for the total amount of drug in the body at distribution equilibrium.

Pattern 1 Distribution Value

• The volume of plasma is 3-4 L, so the value of Vd in pattern 1 is 3-5 L.

Pattern 2 Distribution Value

• Vd value of 30-50 L, corresponding to total body water.

Pattern 3 Distribution Value

• Very large Vd value.
• Chlororoquine has a Vd value of 6500 L.
• Distributes in tissues and organs.

Pattern 4 Distribution Value

• Has a Vd value within a wide range of values.

Distribution of Hydrophilic Drugs

• Hydrophilic drugs, drugs with small or negative log P, and highly charged drugs cannot pass the lipid membrane.
• Their Vd is close to the total volume of water in the body (pattern 2).

Distribution of Lipophilic Drugs

• Lipophilic drugs have no charge and can enter the lipid membrane easily.
• Vd value is larger than total body volume.
• Tricyclic antidepressants are very lipophilic and often have volumes over 1000 L.

Capillary Permeability

• Capillary walls are permeable.
• Lipid-soluble drugs pass-through very rapidly.
• Water-soluble compounds penetrate more slowly at a rate dependent on their size.

Renal vs Brain Capillary

• Renal and hepatic capillaries have increased permeability, are very porous, and allow for extensive distribution.
• Brain capillaries have an impermeable wall with tight junctions (the blood-brain barrier/BBB) and are absent in the nasal route.

Organ Perfusion

• Group I: highly perfused lean tissue (heart, liver, lungs, kidney, brain).
• Group II: poorly perfused lean tissue (muscle and skin).
• Group III: fat.
• Group IV: negligible perfusion (bone).

Ionized drug in the body

• An ionized drug at physiological pH does not cross the cell membrane and has limited distribution, pH drives ionization which drives distribution.

Drug Binding to Plasma Proteins

• Many weak acidic drugs bind to albumin via electrostatic and hydrophobic bonds/interactions.
• Albumin is the most abundant protein in the body.