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Comprehensive Overview of Pharmacokinetics: Absorption, Distribution, and Biotransformation of Drugs

Detailed exploration of drug absorption, membrane transport, types of absorption , bioavailability, distribution, biotransformation and excretion processes essential for understanding drug behavior in the body, including factors affecting absorption, bioavailability, distribution, and biotransformation.

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PHARMACOKINETIC The quantitative study of drug movement in, through and out of the body What body does to drug 2
ABSORPTION 13  Movement of the drug from its site of administration into the circulation It is the process by which unmetabolized drug enters into blood after crossing biological barrier Different biological barriers GIT membrane Nasal, Rectal mucosa skin
MEMBRANE TRANSPORT Cell Membrane/ The Plasma Membrane The cell membrane physically surrounds the cell's contents and acts as a protective barrier separating the inside of the cell from the outside environment. It regulate what can enter from the extrinsic environment into the intrinsic environment of the cell to cause an action or adverse reaction.
Drug walks across → Passive diffusion Carrier holds the drug's hand → Facilitated diffusion ATP "gives energy" to the carrier → Active transport Cell membrane surrounds the drug with arms → Endocytosis
Active transport Primary active transport The active transport of molecules and ions across membrane requires the expenditure of cellular energy (ATP) Carriers move molecules or ion from the side of lower to the side of higher concentration The process transfers only one ion or molecule and in only one direction, and hence called as uniporter example The sodium-potassium pump (Na⁺/K⁺-ATPase) 11
Secondary Active transport • the energy to pump one solute is derived from the downhill movement of another solute (mostly Na+) •Symport or Cotransport : both the solutes move in the same direction example, the movement of glucose along with sodium ions. Thiazide Diuretics act on the Na+/Cl- symporter in the distal convoluted tubule to reduce sodium and chloride reabsorption. •Antiport or Exchange transport: both the solutes move in opposite directions Eg. Na+,Cl – dependent neurotransmitter transporters (NET, SERT) 11
Bioavailability Bioavailability means amount of drug which actually reaches the systemic circulation or site of action from given dosage form after its administration . It determines how much of a dose is actually usable by the body It depends on Drug absorption and on first pass metabolism IV route has 100 % bioavailability since the drug is directly loaded into the systemic circulation
On the other hand The oral route will not bioavailability at Par with iv route since the drug will have to pass to the GI track ,intestine and then pass the first pass metabolism. This will definitely decrease the actual drug reaching the site of absorption and hence the bioavailability
Absorption phase The portion of the curve from the start to the peak (Tmax). Here, the rate of absorption > the rate of elimination, so drug concentration increases. Elimination phase The portion of the curve after the peak (Tmax). Here, the rate of elimination > the rate of absorption, so drug concentration decreases. Onset of action Time when plasma concentration first reaches MEC.
Duration of action: Time for which plasma concentration remains above MEC. Therapeutic range: The range between MEC and MSC where the drug is effective and safe. Toxic level: Concentration above which adverse/toxic effects may occur.
Bioequivalence When the bioavailability of a drug from different formulation is the same then it is called as bio equivalence Two different preparations of a drug are considered bioequivalent when the rate and extent of bioavailability of the active drug from them is not significantly different under suitable test conditions 14
14 Bioequivalence If Cmax , Tmax , and AUC are sufficiently similar, the test product is considered bioequivalent to the marketed product. ** Bioequivalence does not mean the two curves must be exactly identical; they need to fall within the accepted regulatory bioequivalence limits.
Bioavailability Bioequivalence The fraction of an administered dose that reaches the systemic circulation. Comparison of two formulations to determine whether they have the same rate and extent of absorption. Example: Compare Oral Pantoprazole 40 mg with IV Pantoprazole 40 mg. Example: Compare Generic Paracetamol 500 mg with Crocin 500 mg (brand). Oral Pantoprazole has ~77% bioavailability, whereas IV Pantoprazole has 100% bioavailability. If the generic and Crocin have similar AUC, Cmax, and Tmax (within regulatory limits), they are considered bioequivalent. How much of the drug reaches the bloodstream? Do two formulations behave the same in the body?
Factors affecting Bioavailability/Absorption of drugs Pharmaceutical factors 1. Physical state of drug 2. Particle size 3. Molecular weight 4. Concentration 5. Dissolution rate 6. Absorbing surface 7. pH 8. Formulation 9. Lipid solubility 10. Degree of Ionization. ** Colorful text indicates factors affecting both bioavailability and absorption; black text indicates factors affecting bioavailability only.
1. Food and other substances 2. Functional integrity of G.I.T. 3. First pass metabolism 4. Gastric emptying time and gastrointestinal motility 5. Disease state of gut/GIT diseases 6. Drug- drug interaction Factors affecting Bioavailability/Absorption of drugs Pharmacological factors ** Colorful text indicates factors affecting both bioavailability and absorption; black text indicates factors affecting bioavailability only.
Distribution of drugs After absorption drug passes through various fluid compartment such as Plasma interstitial fluid compartment  transcellular fluid compartment ( cerebrospinal fluid) cellular fluid compartment
Distribution of drugs 1. After absorption some drugs diffuse through the cell membrane some remain on the membrane itself while some others are distributed in the cellular fluid 2. Certain drugs are bound to the plasma proteins while some others remain in the extracellular fluid in free state . 3. Some drugs are also stored in different tissues of the body including bones, liver, fatty tissues.
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Distribution of drugs Fat soluble drugs --- stored in adipose tissue Water soluble – distributed in extracellular space Acidic Drugs--binds with plasma albumin Basic drugs - --muscle cells, α1 acid glycoprotein, globulin
Distribution of drugs Lipid-soluble drugs cross cell membranes easily → distribute widely into ICF Water-soluble drugs remain mainly in ECF (plasma and interstitial fluid) Only the unbound (free) fraction of a drug distributes into body fluids and reaches the site of action Changes in body water (e.g., dehydration, edema) can alter volume of distribution and drug levels.
Highly plasma protein bound drugs are largely restricted to the vascular compartment. The bound fraction is not available for action. However, it is in equilibrium with the free drug in plasma High degree of protein binding generally makes the drug long acting. One drug can bind to many sites on the albumin molecule In hypoalbuminemia, binding may be reduced and high concentrations of free drug may be attained
Factors affecting drugs distribution Physiological factors 1. Cardiac Output 2. Regional Blood Flow 3. Capillary Permeability 4. Tissue Volume 5. Special Tissue Characteristics Such As BBB Physicochemical properties of drug 1. binding to drug plasma protein 2. binding to other tissues like Fat, bone, liver 3. Affinity for tissue constituents 4. Tissue redistribution
Factors affecting drugs distribution • Initially drug gets distributed to the organs which are highly perfused (kidneys, liver, brain) • Organs like muscles, Skin, and fat received less blood flow and hence less drugs • After initial quick distribution the second phase of distribution may require minutes to several hours before equilibrium between tissue concentration and blood concentration is achieved
Physicochemical properties of drug • Diffusion of drugs into tissue fluid occurs rapidly as the capillary endothelium is highly permeable. • However , this blood tissue partitioning depends on the binding drug to plasma protein • The fraction of total drugs bound with plasma protein depends on concentration and affinity of binding sites of drug
Physicochemical properties of drug • Only free drug can diffuse out and available for pharmacological effect • While plasma bound drug remain in blood and this act as reservoir of drug • Fat tissue, bone, liver also act as reservoir of drug
Biotransformation of drugs • Biotransformation of drugs involves altering the physical and chemical properties of drugs within the body. • Biotransformation of drugs usually occurs in two phases. 1. Phase I is known for functionalization reactions 2. Phase II is defined by biosynthetic or conjugation reactions
Purpose of biotransformation it helps convert toxic compounds such as xenobiotics into less harmful substances readily excreted from the body. It also aids in modifying substrates such as drugs into a form that the body can easily use. The most important function of biotransformation is to convert non- ionised , lipid soluble drugs into more polar, water-soluble compounds so that their elimination through the urine is easy
Prodrugs: after pharmacological transformation active compound may formed in vivo. After biotransformation inactive substances may act as prodrugs Castor oil- ricinolic acid Diazepam-Oxazepam Prednisone--Prednisolone Active drug may be converted into toxic substance Parathion - paraxon
Non-Synthetic reactions (phase 1 reactions) • Enzyme carry out oxidation, reduction and hydrolysis reactions • Includes introduce functional groups such as -OH, - COOH, - SH, -O- , NH2 etc • Phase 1 reactions lead to inactivation of active drug • In certain exceptions may lead to bio-activation of drug • Phase 1 biotransformation is referred to as functionalization phase of drug metabolism • Cytochrome P450 isoenzymes , flavin containing monooxygenases (FMO) , epoxide hydrolases (EH)
• Synthetic reactions (phase 2 reactions) • Metabolite formed in phase 1 reactions form the substrate for phase 2 reaction • Metabolites of phase 2 reactions are more water soluble and targeted either excrete in urine or bile • UDP- Glucouronasyl transferases (UGT)- glucouronic acid • Sulfotransferases – sulphate • Glutathione –S- transferases -- Glutathione
• Xenobiotics : drugs • Extensively metabolised and eliminated so that they do not cause harm to body • Liver: major site of metabolism • Endogeneous (cholesterol, steroids, fatty acids and proteins) and Xenobiotics
Factors influencing the drug metabolism 1. Genetic factors 2. Environmental factors 3. Inhibition of metabolism 4. Induction of metabolism 5. Disease state of individual 6. Drug -drug interactions 7. Drug -food interaction 8. Nutritional status of individual
Genetic factors • Genetic makeups play important role in drug metabolism Acetylation is a Phase II conjugation reaction Where the liver enzyme N-acetyltransferase 2 (NAT2) attaches an acetyl group to a drug molecule to make it easier for the body to excrete Due to inherited changes in the NAT2 gene sequence (genetic polymorphism), The human population is divided into two major metabolic phenotypes: Fast (Rapid) Acetylators and Slow Acetylators.
Isoniazid (Anti-Tuberculosis Drug) Slow Acetylators Drug stays in the body a long time Causes nerve damage with numbness or tingling (peripheral neuropathy) Leads to a severe lack of vitamin B6 Fast Acetylators Body clears the drug out too fast. Standard doses do not kill the bacteria Leads to treatment failure or drug resistance
Slow Acetylators • Slower clearance causes accumulation of the drug in tissues. • This significantly increases a patient's risk for severe, idiosyncratic hypersensitivity reactions, drug rashes, and bone marrow toxicity Fast Acetylators • Produce large amounts of acetylated metabolites quickly. • In poorly hydrated patients, these fast acetylators face a risk of crystalluria Sulfonamide Antibiotics (e.g., Sulfamethoxazole, Sulfapyridine) Sulfonamides are primary aromatic amines requiring NAT2 to attach an acetyl gr for renal excretion.
Environmental factors Drugs or Environmental toxins can induce hepatic microsomal enzyme oxidising system or CYP450 resulting into rapid metabolism and elimination of drug The environmental pollutants like pesticides can induce metabolism
Drug -food interaction Caused by nutrients altering enzyme activity. Tyramine present in cheese, banana may not be metabolised by MAO if MAOI (MAO - inhibitor) is given and severe hypertensive crisis may result When a person takes a Monoamine Oxidase Inhibitor (MAOI), the body cannot break down dietary tyramine. This triggers a severe, life-threatening hypertensive crisis, a phenomenon famously known in pharmacology as the "cheese reaction.“
Grapefruit juice blocks intestinal CYP3A4 enzymes. If you drink a glass of grapefruit juice, its constituent bind irreversibly and deactivate the CYP3A4 enzymes in your gut. Because the enzymes are disabled, almost the entire dose of simvastatin floods into your bloodstream. This mimics a massive drug overdose. High blood levels of statins cause severe muscle toxicity, Kidney Failure Severe Muscle Pain: Debilitating weakness and cramping.
Nutritional status of individual The drug oxidation rate is severely decreased in malnourished children and elderly. High protein diet act as metabolising enzymes inducers Vitamin deficiencies impair crucial biochemical pathways Low protein diets reduce enzyme synthesis
Disease state of individual In liver cirrhosis metabolism of drug is severely reduce resulting in drug toxicity. In kidney disease, decreased elimination of drug metabolites is observed
Inhibition of metabolism Isoniazid inhibits the hydroxylation of diphenyl hydantoin and may cause toxicity of diphenyl hydantoin Induction of metabolism Barbiturates stimulate microsomal enzyme system in the liver and thus increases the metabolic degradation of other drugs like alcohol, phenytoin
Drug -drug interactions Simultaneous administration of two drugs causing interactions may show either inhibition of metabolism of one the drugs or induction of metabolism
Excretion of drugs Kidneys : Majority of drugs are excreted in urine. Drugs in the urine are excreted by passive glomerular filtration, active tubular secretion and passive diffusion across the wall of nephrons Excretion of acidic and basic drugs depends on pHof urine Weak acids are quickly excreted in alkaline urine and weak bases are quickly excreted in acidic urine Helpful in drug poisoning
Lungs Various gaseous inhalants General anaesthetics , paraldehyde and alcohol Intestine Purgative like senna, cascara bark are partly excreted in the intestine after desired action on large intestine. Heavy metals
Skin: Arsenic and Lead are eliminated by skin in minute quantities Arsenic gets deposited in the hair follicles Milk: Antibiotics , Morphine, thiourasil compounds, sulphonamides are excreted in milk Bile: Erythromicin and novobiocin are eliminated in the bile and reabsorbed again in intestine Prolong the action of drug by the enterohepatic circulation
📖 Explore More: Pharmacokinetics Video link Topic Video 1 https://youtu.be/0d2F-GKSVYw Pharmacokinetics Overview, Absorption & Bioavailability Video 2 https://youtu.be/Fzh8mOOYywo?si=QxBI pOpLQUNtN79U Drug Metabolism / Biotransformation Video 3 https://youtu.be/SZ3BZBBC-Qc?si=sVkhh 8YeFxkriNW6 Urine Formation, Kidney & Nephron Function — useful for understanding drug excretion Video 4 https://youtu.be/Y2N8iQ2Khxg? si=bhxSfEawjfLZrhfx Drug Distribution / How Medications Reach Target Sites
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