PRACTICUM 4: DETERMINATION OF PHARMACOKINETIC PARAMETERS OF DRUGS THROUGH ADMINISTRATION INTRAVENOUSLY (MODELIN VITRO) Description of Theory In general, drugs can be given intravascularly (directly into thein blood vessels) and extravascular (outside blood vessels such as oral, rectal administration, intramuscular injection, etc.). Given extravascularly, the drug will enter the circulatory system through the absorption process.Intravascular administration can be done as a bolus (all at once like an intravenous injection) or continuously at a constant rate like an infusion. After entering the circulatory system, the drug will undergo a process of distribution, metabolism and excretion. The processes of "metabolism" and "excretion" are elimination processes. These various processes will cause changes in blood drug levels over time. Through a mathematical modeling approach, drug kinetics in the blood can be described using a compartmental model: one compartment and multi-compartment. When administered intravenously, the entire drug will enter the circulatory system at once so that at the time of administration, the drug level in the blood is the highest and the drug level will decrease due to the distribution process into other tissues and elimination.The equation for the kinetics of drug in the blood during intravenous bolus administration with a dose D that follows the one-compartment model is given by the following equation: Cpt= C0 . ℮-kt where Cpt is the drug concentration in time t, C0is the drug concentration at time 0, k or ke is the drug elimination rate constant. By determining drug levels at various times, the price of C0and k can be calculated by linear regression after the equation is transformed into logarithmic values: Iog Cpt = Iog C0– k/2,303.t After determining the value of C0and k, various pharmacokinetic parameters of the drug related to the method of administration of the drug by intravenous bolus can be calculated. Pharmacokinetics is knowledge that studies the state of drugs and their metabolites in living organisms as a function of time after the absorption, distribution, metabolism and excretion processes. Determination of drug concentrations in blood is generally carried out in plasma or serum by assuming that drug levels in plasma have a dynamic balance with drug levels in tissue, so changes in drug concentration in plasma will be able to reflect changes in drug levels in tissue. Data on drug concentrations in plasma as a function of time will provide a comprehensive picture of drug kinetics in the body after drug administration via a particular route. Based on the curve of the relationship between concentration and time, the pharmacokinetic model followed by the drug can be identified and the pharmacokinetic parameters can be calculated. Drugs that enter the body can follow several pharmacokinetic models. The most widely used models are compartment models, which consist of single open compartment models and multi-compartment models. Peak concentration parameters (Cmax) is a parameter that states the maximum concentration that a drug can reach in plasma. This parameter is related to dose, absorption rate constant and elimination rate constant of the drug. Time to reach peak concentration (Tmax) is a parameter that describes the absorption speeddrug. These two parameters can be determined from the curve. The area under the curve from time t = 0 to t = ∞ is a parameter that describes the amount of drug absorbed (AUC). To calculate this parameter, the trapezoidal method and the pharmacokinetic equation can be used.These three parameters are usually used to assess whether a medicinal preparation has good bioavailability. Elimination half-life parameters (t1/2) can be used to adjust the dosage regimen of a drug. Implementation of Practicum a. Tools and materials Tools: Scientific calculator, Beacker with tap, separating funnel, Beacker glass,magnetic stirrer, static Materials: Vitamin C, Aquadest, semilog paper, worksheet b. Work procedures The following experiment is a simulation of intravenous bolus drug administration by taking a drug compound as a model (Vitamin C 100 mg/10 mL). The drug solution (considered an injection preparation) is administered all at once (bolus) into a container (considered the blood compartment). The fluid in the container will then be excreted at a constant rate (considered a renal excretion process). The fluid lost due to excretion is then replaced with water (considered drinking water). 1. Fill a container with 250 mL of aqua destillata. 2. Make a certain volume of drug solution; put it all at once into the container. 3. Run the peristaltic pump/faucet immediately to remove the liquid from the container and the peristaltic pump to replace the lost water from the container. 4. Take 5 mL samples at 5, 10, 15, 30, 45, 60 and 90 minutes after the series is run. Each time you take a sample, add a volume of water equal to the volume of the sample (1 mL/ 100 mL). 5. Determine the drug level in the sample (spectrophotometrically). 6. Plot drug level data against time on semilogarithmic paper. 7. Determine the drug compartment model 8. Calculate the value of Co, elimination constant, Vd, Cl and T1/2.