Introduction to Biopharmaceutics PDF

**Introduction to Biopharmaceutics** **Biopharmaceutics** - Study of how the physiochemical properties of the drug, dosage forms and route of administration affect the rate and extent of drug absorption - Pharmacokinetics is the study and characterization of the time course of dru...

**Introduction to Biopharmaceutics** **Biopharmaceutics** - Study of how the physiochemical properties of the drug, dosage forms and route of administration affect the rate and extent of drug absorption - Pharmacokinetics is the study and characterization of the time course of drug absorption, distribution, metabolism and elimination - Pharmacodynamics is the study of the biochemical and physiological effects of the drug on the body - Absorption - Distribution - Metabolism - Excretion: kidney - Polar drugs in urine -- if necessary, liver metabolises drug to more polar - Distribution governed by affinity for various tissues. Depends on: - Aqueous or lipid solubility - Binding to extracellular substances -- e.g. proteins - Intracellular uptake **Summary of ADME** A diagram of a drug distribution Description automatically generated **Absorption -- HOW?** - **[Passive diffusion]** - Movement via concentration gradient across a membrane separating two body compartments - Does not involve a carrier, is not saturable and shows a low structural specificity - Majority of drugs gain access to body - Cell membranes of living organisms are composed of a lipid bilayer (also for sub-cellular structures) - Barrier that keeps ions, proteins and other molecules from diffusing out or into cells. Impermeable to most water-soluble molecules -- e.g. ions (cells need to regulate salt concentrations and pH by pumping ions across their membranes using ion pumps) - Natural bilayers are usually made mostly of phospholipids, which have a hydrophilic head and two hydrophobic tails - Polar molecules have low solubility in the hydrocarbon core of a lipid bilayer and hence have low permeability coefficients across the bilayer. **Lipid-soluble drugs readily move across most biological membranes** **hydrocarbon** chains + **hydrophilic** head - **A lipid-aqueous drug partition coefficient** describes the ease with which a drug moves between aqueous and lipid environments - The ionisation state of a drug is an important factor in determining how well the drug will move across a lipid membrane: charged drugs diffuse through lipid environments with difficulty - The pH and the drug pKa (determined using the Henderson-Hasselbalch equation) are important in determining the drug's ionisation state, and will significantly affect transport - **Water soluble drugs** - Penetrate the cell membrane through aqueous channels - Lipid bilayer of cell membrane -- serve as primary barrier - **[Facilitated diffusion]** (no extra energy needed): - Involves carrier proteins, and it is **a saturable process** e.g. large water soluble/polar compounds - **[Active transport]**: - Requires energy - Transport is probably against the concentration gradient - Active transport is a particularly important mechanism for **passage of larger drug molecules** - Carrier involved -- e.g. levodopa - **[Endocytosis and exocytosis]** - These processes mediate entry into cells by very large substances - Ex) movement across intestinal wall into blood of vitamin B12 complexed with its binding protein e.g. solid particles/oil particles, 1-100 nm **Bioavailability** how much drug get into the blood - Therapeutic response on a drug depends on adequate concentration at site of action - Adjust plasma concentration -- adjust response therapeutic response should be related to the concentration - Be careful -- drug may be bound to plasma proteins and not available (inactive) - Bioavailability is a measure of the amount of drug from a formulation that appears in the plasma (systemic circulation) = how much drug actually get into the blood (absorbed) i.e. measure of the rate and extent of absorption - Calculated by determining the AUC from a blood plasma drug concentration versus time plot - Non-IV (non-intravenous): ranges from 0 no drug in the blood -- metabolised in kidney to 100% unlikely - IV (intravenous): 100% **Single oral dose** A diagram of a function Description automatically generated blood plasma concentration → drug appearing in the blood - **Single oral dose of drug** - Blood samples withdrawn periodically and concentration of drug analysed - Initial rise = absorption phase, rate of drug absorption \> rate of drug elimination - Peak = [*C*~max~]{.math.inline}, rate of absorption = rate of elimination → turning point of the graph ㄴstill likely to have a little bit of drug left to be absorbed/some drug getting absorbed as going down → eventually complete absorption -- pure elimination (no more input of drug)/concentration will half in a definite time = **half-life (exponential)** / tmax = time it takes to reach to Cmax - Elimination phase, elimination \> absorption after Cmax -- elimination P is prolonged(not symmetrical graph) - Eventually, no more absorption, elimination is exponential (first order) - MEC = minimum effective concentration -- minimum concentration required for desired pharmacological effect exceed/reach to show any clinical effects/make it as small as possible (to widen the therapeutic window) - MSC = maximum safe concentration -- above which toxic effects occur regular blood check to make sure not exceeding - Therapeutic window -- desired response with no toxic effects (between MEC and MSC) - Pharmacokinetic parameters; 1. Cmax 2. Tmax 3. Entire area of the curve (not just therapeutic window/between two limits) -- the value of the availability (total amount of absorption) 4. **Half-life** (elimination part) time it takes to the conc to half its value -- at pure E, no more drug is absorbed (how long drug will gonna stay in our body -- dosing) **Factors influencing bioavailability** A diagram of a diagram of a different way Description automatically generated with medium confidence **Drug absorption for 3 formulations of the same drug** - Similar AUC for A and B - the area of the curve A=B, but different actions/results of each (we have to reach at least MEC to MSC to get clinical effects) - **A** exceed the MSC -- give some toxic effects - **B** is in the therapeutic window -- get some effects we want - **C** could not make it to reach MEC -- no clinical effects - More information needed (bioavailability is not enough) - Cmax and tmax are different ! **Bioequivalence** use pharmacokinetics parameters to market authorization - Comparing if two dosage forms containing the same drug are equivalent in terms of rate and extent of absorption - Use AUC, [*C*~max~]{.math.inline} and [*t*~max~]{.math.inline} - Limits 80-120% difference. Depends on safety and therapeutics - **Regular drug dosing (computer simulation)**  - **The steady state (computer simulation)** A diagram of a drug intake Description automatically generated 0 goes up initially -- concentration compounds/go higher after second dose) -- after reach **steady state**, the concentration doesn't go up higher after **repeated doses** (means of the state) -- should be the right time as instructed (take drug every 6 hours = half-life: 6 hours) **Importance of protein binding** In addition, the drug may bind to plasma proteins in the blood, which will further lower the concentration of free (i.e. diffusible) drug in the blood. → Consequently, the blood acts as a 'sink' for absorbed drug and ensures that the concentration of drug in the blood at the site of absorption is low relative to that in the gastrointestinal fluids at the site of absorption (The 'sink' conditions provided by the systemic circulation ensure that a large concentration gradient is maintained across the gastrointestinal membrane during the absorption process) **Oral vs Intravenous** A diagram of a medical procedure Description automatically generated with medium confidence **IV administration**  **\ ** **Absolute bioavailability** - Fraction of administered dose absorbed into the systemic circulation (according for different oral/IV doses) A black text on a white background Description automatically generated - abs = via absorption site - iv = via intravenous bolus injection (100% bioavailable) **Drug distribution** - Drugs may distribute into any or all of the following compartments: - **Plasma** - **Interstitial Fluid** - **Intracellular Fluid** Factors: **Aqueous or lipid solubility** - Only the un-ionised form will diffuse across membrane **Blood flow** - Parts of the body which receive the most blood flow gets the most drug **Volume of distribution (V)** - If put dose of drug in flask, **[dose = vol x conc]** → influenced by its solubility in water & its binding to tissue → not affected by dose being administered e.g. if 2 L flask and conc is 10 mg [*L*^ − 1^]{.math.inline}, the dose would be 2 x 10 = 20 mg - Ex) Two drugs, A and B, given 100 mg IV (intravenously) and then plasma concentration determined, (plasma is fluid part of blood containing proteins -- mainly albumin) i.e. suspended cells removed. About 3 L A = 10 mg [*L*^ − 1^]{.math.inline} B = 1 mg [*L*^ − 1^]{.math.inline} What is the volume of distribution? - A has V = 10 L and B has V = 100 L - **Why?** - **[Water-soluble] drugs or protein** bound drugs will be present in high concentration in plasma Therefore, lower V of distribution loads of drugs staying in blood plasma - **[Lipid-soluble]** lipophilic **drugs or those** bound to tissues will be present in low concentration in plasma Therefore, higher V of distribution - Warfarin, 99% bound to protein, low lipid solubility -- low V (0.14 L/kg) - Chloroquine, 61% protein bound, high lipid solubility -- high V (115 L/kg) **Metabolism** - Metabolism = Biotransformation - Any process which results in a chemical change in a drug in the body - May go in stages, and generally goes from more lipophilic to increasingly hydrophilic for better/effective elimination - A drug may have several metabolites (by products or waste products) - Metabolites may be inactive or active need to know what they do (might be toxic) Dose = Volume x Concentration **Metabolic processes** can occur in any tissue, but are most likely to occur in **liver, kidneys, lungs, and GI tract** - Cleavage - Splitting of the molecule into 2 or more simpler molecules - Oxidation - Combining the molecule with oxygen, or increasing the electropositive charge by the loss of hydrogen or of one or more electrons + increase polarity of drug - Conjugation - The combining of the molecule with glucuronic or sulfuric acid - Reduction - The molecule gains 1 or more electrons and becomes more negatively charged **Elimination** +-----------------------+-----------------------+-----------------------+ | | **Elimination** | | +=======================+=======================+=======================+ | **Major** | **Kidney** | **Liver** | | | | | | | Filtration | Metabolism | | | | | | | Secretion | Secretion | +-----------------------+-----------------------+-----------------------+ | **Minor** | **Others** | **Lungs** | | | | | | | Mother's milk, | Exhalation | | | | | | | sweat, saliva | | +-----------------------+-----------------------+-----------------------+ - Kidney - Glomerular filtration -- Drug crosses the glomerular filter to be excreted - Liver - Change a lipid soluble to more water-soluble molecule to be excreted in kidney - Possibility of active metabolites with same or different properties as parent molecule - Mediated via CYP450 enzyme → can generate active metabolism that may have same or different pharmacological properties **Half-life -- time taken for concentration to decrease to half its value** A diagram of a curve Description automatically generated **Half-life** Choose the part of the exponential graph (we do not know the end point) -- find concentration of t1 and half the conc → find t2 of the halved concentration → distance between t1 and t2 is the **HALF-LIFE** - [*t*~1/2~]{.math.inline} important in determining the frequency of dosing - Drugs with short [*t*~1/2~]{.math.inline} give more frequently -- e.g. every four or six hourly - Drugs with long [*t*~1/2~]{.math.inline} may give once a day - Linear kinetics, elimination rate α concentration i.e. first order kinetics (most drugs) - 1 [*t*~1/2~]{.math.inline} 50% eliminated - 2 [*t*~1/2~]{.math.inline} 75% eliminated - 3 [*t*~1/2~]{.math.inline} 87.5% eliminated - 4 [*t*~1/2~]{.math.inline} 93.75% eliminated - Therefore, after 5 [*t*~1/2~]{.math.inline}, there is over 95% of drug eliminated → Half-life is critical in determining how often a drug should be administered **Half-life Calculation** - Exponential decay  C = concentration at any time (t) [*C*~0~]{.math.inline} = initial concentration [*e*]{.math.inline} = 오일러 constant k = specific death rate - If take natural logs, [ln *C* = ln *C*~0~ − ln *e*^ − *kt*^]{.math.inline} → how conc decrease exponentially over-time in first-order kinetics - Therefore, [ln *C* = ln *C*~0~ − *kt*]{.math.inline} (y = mx + c) or [log *C* = log *C*~0~ − *kt*/2.303]{.math.inline} - Plot of [log *C*]{.math.inline} or [ln *C*]{.math.inline} versus t will give straight line with slope [ − *k*/2.303]{.math.inline} or [ − *k*]{.math.inline} respectively - [ln *C* = ln *C*~0~ − *kt*]{.math.inline} - Therefore, [*kt* = ln *C*~0~ − ln *C* = ln *C*~0~/*C*]{.math.inline} - If [*t* = *t*~1/2~]{.math.inline}, [*C* = *C*~0~/2]{.math.inline} i.e. [kt~1/2~ = ln 2*C*~0~/*C*~0~ = ln 2 = 0.693]{.math.inline} - Therefore, [*t*~1/2~ = 0.693/*k*]{.math.inline} **Summary** - **Biopharmaceutics** is the study (qualitative) of the relationships between physical and chemical properties of the drug and its dosage forms and the biological effects observed following the administration of the drug in its various dosage forms - **Pharmacokinetics** is the quantitative study of the kinetics of drug absorption, distribution, metabolism and excretion (ADME)