Lecture 1 2024 Biopharmaceutics and Pharmacokinetics PDF

Biopharmaceutics and Pharmacokinetics Associate Professor Noha Alaa Dr. Yomna Moussa Outline Biopharmaceutics Pharmacokinetics (ADME) Introduction Introduction Absorption Compartmental models Distr...

Biopharmaceutics and Pharmacokinetics Associate Professor Noha Alaa Dr. Yomna Moussa Outline Biopharmaceutics Pharmacokinetics (ADME) Introduction Introduction Absorption Compartmental models Distribution Multiple dosage regimen Metabolism Analysis of urine data Excretion Bioavailability and Bioequivalence  Lecture 1 Associate Professor Noha Alaa Biopharmaceutics (Intro & Absorption)  Biopharmaceutics ❑ It is the study of the effect of the physicochemical properties of drugs, drug products (dosage form), and the route of administration on drug delivery (the rate and extent of systemic drug absorption) under normal or pathologic conditions. ❑ A primary concern in biopharmaceutics is the bioavailability of drugs. ❑ Bioavailability refers to the measurement of the rate and The aim of biopharmaceutics extent of active drug that becomes available at the site of action. is to adjust the delivery of drugs from the drug product ❑ Bioavailability captures two essential features, namely in such a manner as to how fast the drug enters the systemic circulation (rate of provide optimal therapeutic absorption) and how much of the nominal strength enters the activity and safety for the body (extent of absorption). patient Biopharmaceutical studies allow for the rational design of drug products based on: 1. The physical and chemical properties of the drug substance. 2. The route of drug administration, including the anatomic and physiologic nature of the application site (e.g., oral, topical, injectable…. etc.). 3. The desired pharmacodynamic effect (e.g., immediate or prolonged activity). 4. Toxicologic properties of the drug (MEC, MTC, potent drugs….). 5. Safety & Effect of excipients and dosage form on drug delivery. ❑ For example, Drugs intended for local activity are designed to have a direct pharmacodynamic action without affecting other body organs. These drugs may be applied topically to the skin, nose, eye, mucous membranes, buccal cavity, throat, or rectum. ❑ For a drug administered by an extravascular route (e.g., intramuscular injection), local irritation, drug dissolution, and drug absorption from the intramuscular site are some of the factors that must be considered. ❑ Drug Absorption: It is the process of movement of the drug from its site of administration into the systemic circulation (appearance of the drug in the blood). ❑The effectiveness of the drug can be assessed by its concentration at the site of action. Systemic drug absorption from a drug product consists of a succession of rate processes. 1.Disintegration of the drug product and subsequent release of the drug. 2.Dissolution of the drug in an aqueous environment. 3.Absorption across cell membranes into the systemic circulation. Cell membrane ❑ For systemic absorption, a drug must pass from the absorption site through or around one or more layers of cells to gain access into the general circulation. ❑ The rate at which drug reaches the circulatory system is determined by the slowest step in the sequence. The slowest step in a series of kinetic processes is called the rate-limiting step Poor aqueous solubility: dissolution is often the slowest step and therefore exerts a rate limiting effect on drug bioavailability. In contrast, for a drug that has a high aqueous solubility: the drug crosses or permeates cell membranes is the slowest or rate-limiting step.  Drug absorption Drug Absorption Mechanism of Main factors affecting drug absorption oral absorption 1) Passive Diffusion 2) Carrier-mediated Transport a-Active transport b-Facilitated diffusion 3) Ion pair formation 4) Endocytosis 5) Pore (convective transport) Passive diffusion is the major process for absorption of more than 90% of drugs  Diffusion is the process by which molecules diffuse from a system of higher conc. to a region of lower conc. Through a semi- permeable membrane  Non ionic diffusion  The driving force for passive diffusion is concentration or electrochemical gradient.  Drug movement is a result of the kinetic energy of molecules  Passive as no external energy is expended Fick’s law of diffusion where ; ▪dQ/dt = rate of drug diffusion ( amount /time ) ▪D = diffusion coefficient of the drug constant ▪A = Surface area of the absorbing membrane for drug diffusion ▪Km/w = partition coefficient of the drug between the lipoidal membrane and the aqueous GI fluids constant ▪h = membrane thickness ▪CGIT - Cp = diff. between conc. of drug in GIT fluids & plasma ( Concentration gradient) 1. 1. Energy independent process 2. Greater SA Faster diffusion (Drugs may be absorbed from most areas of the gastrointestinal tract. However, the duodenal area of the small intestine shows the most rapid drug absorption, due to such anatomic features as villi and microvilli, which provide a large surface area. 1. 3. Lesser thickness of the membrane Faster diffusion 4. Higher lipophilicity ( K ) Faster diffusion The driving force for passive diffusion is higher drug concentrations on the mucosal side compared to the blood. because the drug distributes rapidly into a large volume after entering the blood (larger volume = lower concertation), the concentration of drug in the blood initially will be quite low with respect to the concentration at the site of drug absorption (the movement of the blood inside the circulation several times every minute).  The The greater the plasma concentration of the drug …….absorption  2) Carrier-mediated Transport a-Active transport b-Facilitated diffusion a-Active transport It is carrier mediated process where, carrier-drug complex ( bind reversible) crosses the membrane → dissociates the drug → free drug on the other side of the membrane. Trans membrane process Diffusion occurs against conc. gradient Energy consuming process b-Facilitated diffusion It is carrier mediated process where, carrier-drug complex ( bind reversible) crosses the membrane → dissociates the drug → free drug on the other side of the membrane. Trans membrane process However, because this system is carrier-mediated, it is saturable and Diffusion occurs structurally selective for the drug and shows according to competition kinetics for conc. gradient drugs of similar structure. NO energy is required 3) Ion pair formation It is process responsible for absorption of strong electrolytes drugs (charged at all pH) compounds which ionizes at all pH values Drugs are linked to oppositely charged ions → ion pair which behaves as neutral complex have both the required lipophilicity and aqueous solubility for passive diffusion E.g: Propranolol ( Basic drug) forms an ion pair with oleic acid Neutral drug complex diffuses more easily across the membrane 4) Pore (Convective) Transport 1-A transport occurs through protein channel across the lipid membrane of the cell. 2- Very small molecules (such as urea, water, and sugars) are able to cross cell membranes through channels or pores more rapidly than at other parts of the membrane 5) Endocytosis ( vesicular transport) It is a process in which cell absorbs molecules by engulfing them Main factors affecting oral absorption 1. Physical –chemical factors 1. Drug pKa and GIT pH ▪ pH-partition theory The pH-partition theory explains the influence of GI pH and drug pKa on the extent of drug absorption. When a drug is ionized it will not be able to get through the lipid membrane, but only when it is non - ionized and therefore has a higher lipid solubility. The ratio [Unionized U] / [Ionized I] is a function of the pH of the solution and the pKa of the drug; as described by the Henderson - Hassel Bach equation A weakly acidic drug is more likely to be absorbed from the stomach where it is unionized. A weakly basic drug from the intestine where it is predominantly unionized.  Limit Limitations of pH partition theory ✓ Weak acids are also absorbed from the small intestine due to: 1. The significantly larger surface area that is available for absorption in the small intestine in contrast to stomach 2. The longer small intestinal residence time 2. Drug Lipid Solubility: ❑ Drug Lipid Solubility: Barbitone and thiopentone, have similar dissociation constants pKa 7.8 and 7.6 respectively, and therefore similar degrees of ionization at intestinal pH. However, thiopentone is absorbed much more than barbitone. Thiopentone, being more lipid soluble than barbitone, exhibits a greater affinity for the gastrointestinal membrane and is thus far better absorbed. ✓ Doxycycline (Vibramycin) is more lipid soluble than tetracycline ✓ How to be measured? ✓ The drug lipid solubility is measured by its partition coefficient between organic and aqueous phases. ✓ The higher the partition coefficient the more lipid soluble the drug and hence the more absorption is expected given that the drug is capable to dissolve. ❑ Lipid Solubility and Drug absorption: Ideally, drugs should have 1) Sufficient aqueous solubility to dissolve in the fluids at the absorption site. 2) Sufficient lipid solubility to facilitate partitioning of the drug in the lipid membrane. Therefore, should have a perfect hydrophilic-lipophilic balance for optimum bioavailability. 3. Drug Dissolution: In order for absorption to occur, a drug or a therapeutic agent must be present in solution form. This means that drugs administered orally in solid dosage forms (tablet, capsule, etc.) must dissolve in the gastrointestinal (GI) fluids before absorption can occur. ❑ Solubility gives a rough estimation of the completeness of dissolution for a dose of a drug in Solubility pH profile the stomach or the small intestine. 6 Basic 5.6 5.7 ❑ Solubility improved with the addition of an acidic or 5 4.4 Acidic Drug solubility 4 3.6 basic excipient, so, in designing oral dosage forms the 3 2.4 2 2 1.8 formulator must consider that the natural pH 1.2 1 environment of the GIT varies from acidic in the 0 1.2 4.5 6.8 7.4 stomach to slightly alkaline in the small intestine. pH ❑ A basic drug is more soluble in an acidic medium forming a soluble salt. Conversely, an acid drug is e.g. solubility of aspirin is more soluble in the intestine forming a soluble salt at increased by the addition of an the more alkaline pH. alkaline buffer ❑ Biopharmaceutics classification system Factors Affecting the Dissolution Rate: Some of the more important factors that affect the dissolution rate, especially, of slowly dissolving or poorly soluble substances, are: 1.Surface area and particle size. 2.Solubility of drug in the diffusion layer. Salt formation The crystal form of a drug. Complexation. 1- Particle size and surface area ▪ Particle size ᾰ 1/ surface area ▪ Absolute surface area: the total area of solid surface of any particles ▪ Effective surface area : is the area of solid surface exposed to dissolution medium ▪ Larger the surface area , higher the dissolution rate Dissolution take place at the surface of drug, the smaller the particle size, the greater the surface area, enhances water penetration into the particles, the more rapid the dissolution rate Reduction particle size by milling (micronization) ↑ oral absorption & ↓ dose 2- Solubility of the dug in the Diffusion layer A- Salt formation 1. Most drugs either weak acids or weak bases 2. Solubilization technique by salt formation of drugs ✓ Solubility could be affected by: Salt formation: salt of weak acid or weak base. Ex: Sodium salicylate is 550 folds more soluble than the salicylic acid. B- Polymorphism and crystal form of drug ❑ Polymorphism → the arrangement of a drug substance in various crystal forms or polymorphs. ❑ Polymorphs have the same chemical structure but different physical properties, such as solubility, density, hardness, and compression characteristics. ❑ Structurally rigid crystalline forms have much lower aqueous solubility than the amorphous forms (non-crystalline forms). (a) Lowest free energy ❑ Stable polymorph The crystal form that has (b)Highest MP (c) Least aqueous solubility ❑ Metastable polymorph (a) Higher energy state (b) Low MP (c) Highest aqueous solubility ❑ Metastable may convert to a more stable form over time. C- Complexation formation Some drugs form less soluble complexes inside GIT Ex: Tetracycline with calcium ion So Excipients may be added to improve drug solubility as cyclodextrins. 4. Drug permeability Three major properties of drugs affect permeability 2. Polarity of 3. Molecular 1. Lipophilicity drug size of drug 5. Drug Stability, pH and drug absorption Stability pH profile ▪ The stability pH profile is a plot of the reaction rate constant for the drug degradation versus pH. ▪ If drug decomposition occurs by acid or catalysis, some Erythromycin has a pH prediction of degradation of the drug in the GIT may be dependent stability profile made. (e.g. penicillin, erythromycin) ▪ some drugs are susceptible to enzymatic hydrolysis by enzymes located in the GIT (e.g. progesterone, testosterone) ▪ In an acidic medium → decomposition is rapid, in neutral or alkaline pH → stable Enteric coated ❑ To protect against acid degradation in the stomach. Prodrug ❑ Chemical derivatives of the parent drug. ❑ Exhibit limited solubility in gastric fluid but in the small intestine, liberate the parent drug to be absorbed. A drug for oral use may destabilize either during its shelf life or in GIT Reasons ????? 1. Degradation of the drug into inactive form 2. Interaction with one or more different components either of the dosage form or present in GIT to form a complex which is poorly absorbable or un- absorbable  Practical point of view ❑ Even though drugs with greater lipophilicity are better absorbed, it is very important that drugs exhibit some degree of aqueous solubility. ❑ As the biological fluids at the site of absorption are aqueous in nature, therefore the availability of the drug molecule in a solution form is a prerequisite for drug absorption. ❑ Drugs must exhibit a balance between hydrophilicity and lipophilicity. Thank You