Foundations of Molecules to Medicines (PHSI3210) PDF

Foundations of Molecules to Medicines (PHSI3210) ADME: Absorption, Distribution, Metabolism, & Excretion Yazen Alnouti, Ph. D.  ADME -What does the body do to the drug (Pharmacokinetics: PK)? vs. what does the drug do to the body (Pharmacodynamics: PD)?...

Foundations of Molecules to Medicines (PHSI3210) ADME: Absorption, Distribution, Metabolism, & Excretion Yazen Alnouti, Ph. D.  ADME -What does the body do to the drug (Pharmacokinetics: PK)? vs. what does the drug do to the body (Pharmacodynamics: PD)? i. Absorption ii. Distribution iii. Elimination: Metabolism and/ or Excretion 2 Absorption 3  Absorption - Extravascular routes of drug administration require absorption into the systemic circulation before reaching the site of action vs. - Extravascular routes: Oral is the most common vs. others (Intra- muscular, dermal, rectal, inhalational, etc.) - Absorption is bypassed in intravascular (I.V.) & local drug administration (the site of action is localized around the site of administration) routes. - Examples of local drug administration: Oral vancomycin for the treatment of pseudomembranous colitis, topical miconazole cream for the treatment of skin/vaginal..etc fungal infections, intracardiac administration of atropine, intrathecal (epidural) administration of lidocaine, inhalation of steroids via MDIs (vi) lidocaine lozenges, nasal, ophthalmic, ear drops, etc. 4  Oral Absorption - Before the drug is absorbed through the GI walls, it should be available as molecules solubilized in the gastrointestinal (GI) fluids. i. Disintegration: Solid oral pharmaceutical dosage forms undergo disintegration followed by dissolution before they are available for absorption. ii. Dissolution: Liquid oral pharmaceutical dosage forms undergo dissolution before they are available for absorption. iii. Permeability: Penetration of solubilized drug molecules across the GI wall into the portal vein blood and/or lymphatic system. -In general, intestinal >>>> gastric absorption due to larger surface area (200 M2 vs. 1 M2), blood flow (1 L/min vs. 150 ml/min), and transit time (2-5 vs. 10-72 h) 5 Gastrointestinal (GI) System 6 GI Wall Apical, Luminal, Brush Border Side Epithelial Cells (Enterocytes) Basolateral, Blood Side 7  Trans-Membranous Permeability Apical, Luminal, Brush Border Side Passive Diffusion Carrier Mediated Vesicular Transport (Transporters) (Endocytosis) Facilitated Active Trans- Para-cellular diffusion Transport Basolateral, Blood Side 8 Trans-Membranous Permeability i. Passive Diffusion: No energy (ATP) requirements, Unsaturable, Driven by concentration gradient, trans- vs. paracellular ii. Carrier-Mediated Transport: Mediated by transporters, Saturable, Active (requires energy) vs. Facilitated ( driven by concentration gradient) iii. Vesicular Transport: engulfing particles or dissolved material by sacs enclosed by lipid membranes, pinocytosis/ endocytosis/phagocytosis based on size 9  Kinetics of Transport Simple Diffusion Gut Lumen Blood C1 C2 ( 40% homology, subfamilies (letter) with > 60% homology, and 2nd number reflect individual gene product - CYP3A4 isoform is involved in the metabolism of ~50% of all drugs - Induction and inhibition of CYPs is a major source of drug-drug (DDI) and drug-food interactions. - Marked inter-individual variability due to polymorphisms, gender, age, liver diseases, DDI, etc. 29 Fractions of Drugs Metabolized by Various Enzymes P450 UGT Esterases FMO NAT MAO 30 CYP2D6 Polymorphisms 31  Enzyme Kinetics: Michaelis- Menten equation k1 k2 -S+E ES E+P k-1 Vmax[S] v= [S] + Km - n: Reaction Rate/Speed - The higher Vmax, the higher the enzyme capacity & and the more abundant is the enzyme - The lower Km the faster, the reaction & the higher the substrate-enzyme affinity 32  Michaelis-Menten Graphing Vmax Vmax[S] n v= [S] + Km Km [S] - Hyperbolic shape - At [S]>Km, n ~ Vmax, i.e. nonlinear conditions & the PK approaches saturation, n approaches Vmax, (zero order) -At all other [S] in between, full equation, mixed zero-1st order PK, still nonlinear PK 33  Drug-Drug Interactions (DDI) - Other drugs and food can interact with drug metabolism by inhibiting/inducing its metabolism - Enzyme inhibition: Reversible vs. Irreversible I + E+S ES E+P Ki EI - Inhibition decreases enzyme affinity and lowers the Km of victim drugs - Inhibitors strength is measured by Ki, stronger inhibitors have lower Ki and lowers the Km of victim drugs more - Induction typically induces the enzyme expression and increases capacity, i.e. increases Vmax 34  Clearance (Cl) - A convenient way to quantify elimination is clearance (Cl) - Cl is the volume of biological fluid completely cleared from a compound per unit time (volume/time) -Think of a swimming pool-filtering pump: A pump that filters 100 gallons/hr (Cl) will finish clearing a pool faster than a pump that filters 10 gallons/hr - In PK, a drug that has a higher clearance is eliminated faster - Total body/systemic clearance (Cl) is the overall clearance of drug from blood, i.e. the sum of clearances of all eliminating organs - Cltotal = Clexcretion + Clmetabolism = ∑Clall routes e.g. Clrenal + Clliver + Clbiliary + Clintestine…etc 35 Elimination: ii. Excretion 36 Fecal Excretion Fecal Excretion = Nonabsorbed Digesta + Biliary Excretion - Intestinal Reabsorption 37  Liver: Blood/Bile Gate canaliculi Sinusoids 38  Liver: Blood/Bile Gate - Blood leaves the liver through central veins, which merge into the hepatic vein - Biliary canaliculi, which merge into the common hepatic bile duct is another liver outlet - Hepatocytes secrete bile, which contains bile acids, cholesterol, phospholipids, bilirubin, electrolytes, and some metabolites into the canaliculi - Bile is stored in the gallbladder, which is stimulated by cholecystokinin to empty its content into the bile duct, which opens into the duodenum through the sphincter of Oddi 39  Transporters and ADME Metabolism Distribution Elimination Absorption 40 Ho and Kim, Clin Pharmacol Ther. 2005  Enterohepatic Recirculation - Biliary content excreted into the intestine are either excreted into feces or reabsorbed through the intestinal wall into portal vein back to the liver 41  Urinary Excretion = Glomerular Filtration + Active Tubular Secretion - Tubular Reabsorbtion 42 Kidney & Nephron Anatomy 43  Urine flow - Urine formation starts in the bowman’s capsule from blood filtration through the glomerular wall - Urine then passes through the proximal convoluted tubules, loop of henle (descending and ascending limbs), and the distal convoluted tubules - Reabsorption and active secretion take place mainly in this part of the nephron - Urine then passes through collecting tubules, collecting ducts, pelvises, which lead to the ureters 44  Urinary Excretion i. Glomerular Filtration:. Kidneys receive 20-25% of the cardiac output ~ 1.2 L/min (1,700 L/d) ~425-660 ml/min plasma. Glomerular filtration rate (GFR) is the volume of plasma filtered through the glomeruli per unit time ~125-130 ml/min (180 L/d). Filtration fraction (FF) is the % of plasma filtered through the glomeruli (GFR/RPF) ~ 19%. Only the unbound fraction of plasma (fu) content is filtered ii. Tubular Reabsorption. Most of filtered plasma is reabsorbed in renal tubules (98%). Urine flow rate ~ 2 L/ d.. The undissociated forms of acids/bases are more easily reabsorbed.. Urine pH (4.5-8 depending on diet, drug intake, and disease) has a dramatic effect on renal clearance of weak acids and bases. 45  Relationship Between Urine pH & % Ionization for Acids & Bases Urine pH 4 6 8 pKa % Ionization % Ionization % Ionization Acid 2 99.01 99.99 100 4 50 99.01 99.99 6 0.99 50 99.01 8 0.01 0.99 50 10 0 0.01 0.99 Base 2 0.99 0.01 0 4 50 0.99 0.01 6 99.01 50 0.99 8 99.99 99.01 50 10 100 99.99 99.01 e.g. Protein-rich diet, ascorbic acid, NH4Cl acidify urine, whereas carbohydrate, 46 fruit, and vegetable-rich diet, HCO3-, and antacids alkalinize urine  Ex. Methamphetamine: weak base: pKa=9.6 47 Urinary Excretion of Methylamphetamine in Man. A. H. BECKETT & M. ROWLAND. Nature 206, 1260 - 1261 (19 June 1965).  Urinary Excretion iii. Active Tubular Secretion:. Substances can be excreted into urine by active carrier-mediated processes against the concentration gradient - Overall renal clearance (Clr ) = (GFR + secretion rate- reabsorption rate)/ Cp - Clr ranges from 0 to RPF (425-600 ml/min) 48 Foundations of Molecules to Medicines (PHSI3210) PK/PD: Pharmacokinetics/ Pharmacodynamics Yazen Alnouti, Ph. D.  Pharmacokinetics (PK) - Greek “Pharmacon” means drug, and “kinetics” means motion. - Pharmacokinetics (what the body does to a drug) vs. pharmacodynamics (what the drug does to the body). - Clinical PK was largely considered for therapeutic drug monitoring (TDM) to guide individualized drug dosing, adjusting dose to health conditions (liver and kidney diseases), drug-drug interactions (DDI), etc. 50  Rates in Pharmacokinetics - Consider the chemical reaction: 𝐴 ⟶ 𝐵 - Reaction rate is expressed as the disappearance rate of A (-dA/dt) = appearance rate of B (dB/dt) - In PK, the elimination of a drug behaves like a reaction and the elimination rate of a drug is measured by the rate of its disappearance from blood (dC/dt). - Blood samples are frequently collected over time (t), drug concentration is measured (C), C vs. t plots are constructed, curve slope is calculated to determine the rate (dC/dt) Examples of C vs. t Time Profiles Oral Bolus I.V. Bolus Multiple Dosing I.V. Infusion Css Css 52  Zero-Order Kinetics Time C ∆C ∆C/∆t (h) (mg/L) (mg/ml) ∆t (h) (mg/(L.h)) 0 100 - - - 1 90 -10 1 -10 2 80 -10 1 -10 3 70 -10 1 -10 4 60 -10 1 -10 5 50 -10 1 -10 6 40 -10 1 -10 7 30 -10 1 -10 8 20 -10 1 -10 9 10 -10 1 -10 10 0 -10 1 -10 - Elimination rate (dc/dt) = 10 mg/(L.h) - If the drug is eliminated in a constant rate, it has zero-order kinetics  Graphing (zero-order data) - C vs. t profile yields a straight line with a slope = - K and intercept = C0 Intercept: C0 = 100 mg/L - C = C0 - Kt 100 C: blood concentration at any time point (t) 90 80 K: elimination rate constant (conc/ time unit) 70 = 10 mg/(L.h) 60 Slope: dc/dt = C (mg/L) (40-80)/(6-2) = -10 mg/(L.h) = K 50 C0: C at time zero (conc unit) 40 = 100 mg/L 30 20 - Elimination rate (dc/dt) = K….constant 10 0 = 10 mg/(L.h) 0 1 2 3 4 5 6 7 8 9 10 Time (h) - half-life (t0.5) = time it takes for drug concentration to drop by 50%. 1/2 C0 = C0 – K t0.5 …… t0.5 = (C0 - 1/2 C0)/ K = 1/2 C0/ K = 1/2 ×100/ K = 5 h  Example of 1st-Order Kinetics Time C ∆C ∆t ∆C/∆t (∆C/∆t)/C (h) (mg/L) (mg/ml) (h) (mg/(L.h)) (h-1) 0 100 1 74.1 -25.92 1 -25.92 -0.26 2 54.9 -19.20 1 -19.20 -0.26 3 40.7 -14.22 1 -14.22 -0.26 4 30.1 -10.54 1 -10.54 -0.26 5 22.3 -7.81 1 -7.81 -0.26 6 16.5 -5.78 1 -5.78 -0.26 7 12.2 -4.28 1 -4.28 -0.26 8 9.1 -3.17 1 -3.17 -0.26 9 6.7 -2.35 1 -2.35 -0.26 10 5.0 -1.74 1 -1.74 -0.26 - Elimination rate (dc/dt) is not constant, but changing in proportion to C - If the drug is eliminated at a rate proportional to the concentration remaining in blood, it has a 1st order kinetics  Graphing of 1st-order Data (i. C. vs. t) - C vs. t profile does not yield a straight line 100 90 Time C 80 (h) (mg/L) 70 0 100 1 74.1 60 C (mg/L) 2 54.9 3 40.7 50 4 30.1 40 5 22.3 6 16.5 30 7 12.2 20 8 9.1 9 6.7 10 10 5.0 0 0 1 2 3 4 5 6 7 8 9 10 Time (h)  Graphing of 1st-order Data (ii. Ln C vs. t) - Ln C vs. t profile yields a straight line with a slope = - K and intercept = Ln C0 5.0 Intercept: Ln C0 = 4.61 Time C Ln C C0 = 𝑒 4.61 =100 mg/L (h) (mg/L) (mg/L) 4.5 0 100.00 4.61 1 74.08 4.31 4.0 2 54.88 4.01 3.5 3 40.66 3.71 Ln C (mg/L) 4 30.12 3.41 3.0 5 22.31 3.11 2.5 Slope: dLn C/dt = 6 16.53 2.81 7 12.25 2.51 2.0 (2.21-4.01)/(8-2) = -0.3 h-1 = K 8 9.07 2.21 1.5 9 6.72 1.91 10 4.98 1.61 1.0 0.5 - Ln C = Ln C0 - Kt 0.0 K: elimination rate constant (h-1 unit) = 0.3 h-1 0 1 2 3 4 5 Time (h) 6 7 8 9 10 C0: C at time zero (conc unit) = 100 mg/L - half-life (t0.5) = time it takes for drug concentration to drop by 50%. Ln 1/2 C0 = Ln C0 - K t0.5 ……t0.5 = Ln (2) / K = 0.693/ 0.3 = 2.31 h  Graphing of 1st-order Data (iii. Log C vs. t) - Log C vs. t profile yields a straight line with a slope = - K/2.303 and intercept = Log C0 Intercept: Log C0 = 2.0 mg/L Time C Log C C0 = 102 =100 mg/L 2.0 (h) (mg/L) (mg/L) 0 100.00 2.0 1.8 1 74.08 1.9 2 54.88 1.7 1.6 3 40.66 1.6 1.4 4 30.12 1.5 Log C (mg/L) 5 22.31 1.3 1.2 6 16.53 1.2 1.0 Slope: dLog C/dt = 7 12.25 1.1 0.8 (0.96-1.74)/(8-2) = -0.1303 h-1 8 9.07 1.0 9 6.72 0.8 K = -0.1303 * 2.303 = -0.3 h-1 0.6 10 4.98 0.7 0.4 - Log C = Log C0 – (K/2.303)×t 0.2 K: elimination rate constant (h-1 unit) = 0.3 h-1 0.0 0 1 2 3 4 5 6 7 8 9 10 C0: C at time zero (conc unit) = 100 mg/L Time (h) - half-life (t0.5) = time it takes for drug concentration to drop by 50%. Log 1/2 C0 = Log C0 – K/2.303 t0.5 ……t0.5 = Log (2)*2.303 / K = 0.693/ 0.3 = 2.31 h  Graphing of 1st-order Data (iv. Semi-log plot) 1000 - log C= log C0- kt/2.303 - Intercept = C0 , C0 = 100 mg/L Intercept = 100 - Slope = -k/2.303= -0.13, K= 0.3 h-1 - t0.5= 0.693/k = 2.31 h 100 × × × × × Conc (mg/L) × × Slope: dLog C/dt = × × = Log (9.07) – Log (54.88)/(8-2) = -0.1303 h-1 K = -0.1303 * 2.303 = -0.3 h-1 1 0.1 Time 22 0 1 2 3 4 5 6 7 8 9 59  Zero-order Kinetics is Dose/Concentration-Dependent What happens if we double the dose? C (mg/L) 200 10 mg 20 mg D = 10 mg Time (h) Dose Dose 180 D = 20 mg 0 100 200 160 1 90 190 140 2 80 180 C (mg/L) 120 3 70 170 100 4 60 160 80 5 50 150 60 6 40 140 7 30 130 40 8 20 120 20 9 10 110 0 10 0 100 0 1 2 3 4 5 6 7 8 9 10 Time (h) 10 mg Dose 20 mg Dose Elimination rate (dc/dt) 10 mg/(L.h) 10 mg/(L.h) C0: C at time zero 100 mg/L 200 mg/L K 10 mg/(L.h) 10 mg/(L.h) t0.5 5h 10 h - Elimination rate (dc/dt) = 10 mg/(L.h) remained unchanged. Therefore, t0.5, and Cl doubled.  1st-order Kinetics is Dose/Concentration-Independent What happens if we double the dose? C (mg/L) 10 mg 20 mg 200 1000 D =10 mg D =10 mg Time (h) Dose Dose 180 D = 20 mg D = 20 mg 0 100 200 160 1 74 148 140 100 2 55 110 C (mg/L) C (mg/L) 120 3 41 81 100 4 30 60 80 5 22 45 60 10 6 17 33 40 7 12 24 20 8 9 18 0 1 9 7 13 0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10 10 5 10 Time (h) Time (h) 10 mg Dose 20 mg Dose Elimination rate (dc/dt) variable doubles C0: C at time zero 100 mg/L 200 mg/L K 0.3 h-1 0.3 h-1 t0.5 2.31 h 2.31 h - The elimination rate adjusted to the higher dose (dC/dt is proportional to concentration) - Because dC/dt is doubled, the patient was able to keep up with the doubled dose. Therefore, K, t0.5, and Cl remained unchanged.  PK Models/Modeling - PK Model: A mathematical equation that describes the time-course of drug in the body following administration. PK models simulate the concentration vs. time profile in the body - PK Parameter: Constants derived from the coefficients of the PK model - Types of PK Models 1. Compartmental Models 2. Noncompartmental Models 3. Physiologically based PK Models (PBPK)  Compartmental PK Models...... Concentration (C)..... Data Fit One Compartment Ln C........... Time. Time C = Ae -t + Be - t....... Data Fit two Compartments..................... C = Ae -t + Be - t + Ce -t.... Data Fit Three Compartments............ 63  The One-Compartment Model - Most drugs follow the one-compartment model, i.e. monoexponential decay and linear at log-scale. - No physiologic or anatomic meaning - Assumptions of the one-compartment model: i. Rate of elimination is a 1st order process (linear kinetics) ii. Consider the body as a single, kinetically homogenous unit iii. Instantaneous or very fast distribution throughout the body. The drug achieve instantaneous/rapid equilibrium in all tissues and fluids (plasma fast tissues). Does not mean drug concentration in blood equals that in other tissues and fluids. It rather means the rate of change of drug concentration in blood and all other tissues is the same - Drugs start to deviate from the one-compartment model when their distribution between blood and tissues is slow 64  One Compartmental PK Plasma Plasma Tissue 1 Tissue 1 Ln Concentration Tissue 2 Tissue 2 Concentration Time Time 65  Common PK Parameters Cmax AUC Tmax - Cmax, Tmax, & AUC are model independent parameters - t0.5: The time it takes for blood drug concentration to drop by 50%. - Vd: Quantifies the extent to which the drug distributes outside the blood circulation. Higher Vd means higher affinity to tissues - Cl: Quantifies the extent of drug elimination from the body: The rate (volume/time) at which blood is completely cleared from a drug -F: Quantifies the extent of drug is absorbed into systemic circulation after administration via extravascular routes 66 (AUCextravascular/ AUCi.v.)  Basic PK Calculations - The best line/ curve is drawn to best fit the data using regression analysis - K, AUC, & C0 are determined from the C vs. t plot Intercept = C0 × × × × Conc (mg/L) × Slope: dLog C/dt = × = Log (C2) – Log (C1)/(t2-t1) × × K (h-1) = -slope * 2.303 67 Time 22 Basic PK Calculations 0.693 t 0.5 = K D Vd = = C0 Cl K F×D Cl = K × Vd = AUC 68  PD : Receptor Occupation Rate Theory k1 k2 C+R RC E k-1 - C: Concentration of free drug at the receptor site - R: Concentration of the receptor - Rtotal = Rfree + RC - RC: Concentration of the receptor-drug complex - E: Effect (pharmacological response) - E is proportional to the rate of RC formation 69 PD Models: Definitions Emax A B C E D Log Conc -A & B are full agonists -C is a partial agonist -D is an antagonist -Efficacy: A = B > C > D -Potency: C > A > B 70  Rationale for PK/PD Modeling - Pharmacodynamics (PD):. The relationship between free drug concentration at the site of action (receptor) and the pharmacologic response. What the drug does to the body - Pharmacokinetics (PK):. The relationship between the dose and the time course of concentration of a drug in body fluids. What the body does to the drug - PK/PD modeling. Combine both approaches to describe the time-body fluid concentration-pharmacological response course 71  PK, PD, and PK/PD (What are they?) Pharmacokinetics Pharmacodynamics Concentration What the body does to drug? What the drug does to body? Plasma Effect Time Log Concentration PK/PD Effect 72 Time  PK/PD: E vs. Time Profile The activity of IV 01-0.2 mg/kg (+) tubocurarine in unanesthetized volunteers can be monitored as percent depression of muscular activity in different muscles E=mlnCp lnC0 lnC =lnC0 -Kt p p E0(hl) E = E0 – mKt E0(hg) mhlK K Head lift mhgK lnC E Plasma conc E0(if) m Hand grip K E mifK Conc at target site Inspiratory flow Time (min) lnCplasma Time (min) If equilibrium is rapidly achieved between Cp and effect, the effect will be seen immediately. Effect is directly or instantaneously related to plasma conc. 73