Pharmacokinetics (Distribution) PDF

9/10/2024 Pharmacokinetics (Distribution) Fadi Khasawneh, Ph.D. (361) 221-0755 [email protected] 1 Learning Outcomes Describe the process of drug distribution. Know the...

9/10/2024 Pharmacokinetics (Distribution) Fadi Khasawneh, Ph.D. (361) 221-0755 [email protected] 1 Learning Outcomes Describe the process of drug distribution. Know the various fluid compartments in the human body. Understand the difference between one-, two- and multiple-compartment models. Understand the influence of plasma protein binding on drug distribution. Understand the relationship between protein & tissue binding with drug distribution. Define the process of drug elimination. Be able to read the pharmacokinetic parameters of a drug package insert. To be able to understand and use pharmacokinetic parameters such as volume of distribution, clearance and half-life. Understand the concepts of drug accumulation and steady state. Understand the concept of dosing regimens and know how to individualize a dosage in renal or hepatic disease. Understand the relationship between drug distribution and Enterohepatic Recycling, Biliary & Fecal Excretion. 2 1  9/10/2024 Distribution Once a drug begins to be absorbed, it undergoes various transport processes which deliver it to various body areas (liver, kidney, skeletal muscle, bone, brain, etc.) away from the absorption site. These transport processes are referred to as drug distribution and are evidenced by the changing concentrations of drug in various body tissues and fluids. 3 Distribution of Fluid Compartments The majority of the body (60%) is water. 4 2  9/10/2024 One-Compartment Model The whole body (including Drug Compartment each organ) is regarded as Dose one compartment. It is the simplest and most Elimination useful model. Drugs usually are eliminated exponentially. Elimination Whole Body 5 One Compartment Model The concentration-time profile/course following an IV bolus injection Co Concentration Plasma Drug AUC Time 6 3  9/10/2024 Two-Compartment Model For some drugs, two-compartment An example model describes their pharmacokinetics better. Central Peripheral Compartment Compartment Heart Fat tissue Organs and tissues in which drug distribution is similar are grouped Liver Muscle tissue together into one compartment. Lung Cerebrospinal Kidney Fluid Two compartments are included: a Blood Etc. central compartment and a peripheral compartment. 7 Two-Compartment Model Two phases in the concentration-time profile – A fast distribution phase – A slow elimination phase Distribution Elimination Peripheral Central Compartment Compartment 8 4  9/10/2024 Multi-Compartment Model More than two compartments involved Less commonly used 9 Distribution - Factors that affect extent and rate of drug distribution:  The physicochemical nature of the drug  Organ perfusion rate  Permeability of tissue membranes  Plasma protein binding of the drug  Tissue binding of the drug 10 5  9/10/2024 Principle on Drug Distribution Only the unionized and unbound (free) form of the drug can permeate across biological membranes. 11 Protein Binding Affects the distribution of drug. Many drugs are bound to plasma proteins  To albumin for acidic drugs (e.g., salicylates)  To 1-acid glycoprotein for basic drugs (e.g., propranolol) Binding to other plasma proteins generally occurs to a much smaller extent. 12 6  9/10/2024 Characteristics of Protein Binding Protein binding is reversible. Protein binding is saturable (capacity-limited) at high drug concentrations. However, for most drugs, the therapeutic range of plasma concentrations is limited. Therefore, percent bound is constant. + Protein Drug Protein-Drug Complex (Unbound) (Bound) 13 Tissue Binding Many drugs accumulate in tissues at higher concentrations than those in the extracellular fluids and blood.  The concentration of quinacrine (an antimalarial agent) in the liver may be several thousand-fold higher than that in the blood. Tissue binding usually occurs with cellular constituents such as proteins, phospholipids, or nuclear proteins. Tissue binding generally is reversible. Tissue-bound drug may serve as a reservoir. 14 7  9/10/2024 Principles on Distribution A drug with high plasma protein binding usually has a small volume of distribution. A drug with high tissue binding tends to have a large volume of distribution. 15 Elimination The process of drug (xenobiotics) removal from the body Two major processes and responsible organs  Metabolism – the liver  Excretion – the kidney (major), the bile, etc. Cin Organ of Cout Elimination (liver, kidney) Amount of Drug Eliminated 16 8  9/10/2024 PK Profiles An example Concentration or 17 Important PK Parameters Volume of distribution (Vd) Clearance (CL) Half-life (t1/2) 18 9  9/10/2024 Volume of Distribution (Vd) The volume of distribution (Vd) relates the amount of drug in the body to the concentration of drug in blood or plasma C: 19 Extrapolation Vd is an apparent or imaginary term. It does not relate to real physiological volume of an organ. Vd can vastly exceed any physical volume in the body because it is the volume apparently necessary to contain the amount of the drug homogeneously at the concentration found in the blood or plasma. 20 10  9/10/2024 Volume of Distribution (Vd) Physical volumes for a 70 kg person  Total body water: 42 L  Extracellular water: 17.5 L or 14 L  Blood: 5.6 L  Plasma: 2.8 L Examples  Vd of digoxin : 500 L  Vd of chloroquine: 13000 L  Vd of gentamicin: 18 L Drugs with high Vd values are not homogeneously distributed in the body. 21 Clearance (CL) Clearance is a measure of the body’s efficiency in eliminating drug. Clearance is the single most important factor determining drug concentrations. Clearance of a drug is the factor that predicts the rate of elimination in relation to the drug concentration: Clearance is additive: 22 11  9/10/2024 23 Clearance (CL) There are four major factors that may affect clearance:  The dose  Some drugs (e.g., ethanol) exhibit capacity-limited elimination.  The organ blood flow  Some drugs (high-extraction drugs, e.g., lidocaine) are rapidly cleared by the organ of elimination.  The intrinsic function of the liver or kidneys  The unbound fraction of drug 24 12  9/10/2024 Protein Binding And Clearance 25 Half-life (t1/2 or T1/2) Half-life is the time required to change the amount of drug in the body by one-half during elimination or during a constant IV infusion. In the simplest and most useful case, the body may be considered as a single compartment of a size equal to Vd and drug decay follows first order kinetics. The time course of drug in the body will depend on both Vd and CL: or KE : Elimination constant 26 13  9/10/2024 Half-life (t1/2) Half-life is useful because it indicates the time needed to decay 50% from any concentration following drug administration by any route. Half-life is also useful in IV infusion because it indicates the time required to attain 50% of steady state concentration – or to decay 50% from steady-state conditions – after a change in the dosing rate. 27 Half-life (t1/2) Fundamental pharmacokinetic relations for repeated oral administration of drugs. Steady State Concentration (Css) is achieved after approximately four (4) half lives/times. 28 14  9/10/2024 Examples (Table 3-1) Drug Oral Urinary Bound in Clearance Volume of Half- Target Toxic BA excretion plasma (L/h distribution life (h) conc. conc. (%) (%) (%) /70 kg) (L/70 kg) Acetominophen 88 3 0 21 67 2 15 >300 mg/ml mg/ml Amoxicillin 93 86 18 10.8 15 1.7 - - Atenolol 56 94 5 10.2 67 6.1 1 - mg/ml Digoxin 70 60 25 7 500 50 1 ng/ml >2 ng/ml 29 Package Insert: Ambien 30 15  9/10/2024 Package Insert: Ambien 31 Drug Accumulation 32 16  9/10/2024 Steady State Fundamental pharmacokinetic relationships for repeated administration of drugs. 33 Therapeutic, Subtherapeutic, and Toxic Drug Dosing 34 17  9/10/2024 Individualizing Dosage in Renal or Hepatic Disease 35 Biliary and Fecal Excretion Active transport systems analogous to those in the kidney also are present in the canalicular membrane of the hepatocyte. These systems secrete drugs and metabolites into the bile. Ultimately, drugs and metabolites are released into the intestinal tract during the digestive process. Direct active secretion of drugs and metabolites may also occur from the systemic circulation into the intestinal lumen. 36 18  9/10/2024 Enterohepatic Recycling Subsequently, drugs and metabolites can be reabsorbed back into the body from the intestine - a process termed enterohepatic recycling. Enterohepatic recycling, if extensive, may prolong significantly the presence of a drug and its effects within the body prior to elimination by other pathways. 37 Where drugs go influences How Long Drugs Last In the Body : Raloxifene [Evista®]) (for treatment of osteoporosis in postmenopausal women) is transported by the liver into the intestines where it is reabsorbed (enterohepatic recirculation). This greatly increases the time raloxifene lasts in the body. 38 19  9/10/2024 Any questions? The End 39 20