This is the process of drug disposition in the body, studying the relationship between the processes of drug absorption (A), distribution (D), metabolism (M), excretion (E) and time. This requires us to introduce various parameters to quantitatively describe and predict these processes. (As a soldier fighting on the front line of new drug research and development, it is more reliable to memorize these pieces, only by understanding these parameters, when you participate in various project meetings of the company, you will not be sleepy, but still work hard to check those English words that the leaders pop out······).
Parameters related to absorption process (A)
Area under curve (AUC): The area under the blood drug concentration-time curve reflects the relative amount of drug absorbed into the circulation. (Theoretically it is the area under the drug-time curve from t0 to t∞).
Peak time Tmax: The time to reach peak concentration determines how fast or slow the drug exerts its therapeutic effect or produces adverse reactions.
Peak concentration Cmax: The peak concentration of the drug in the body determines whether the drug exerts its therapeutic effect or produces adverse reactions.
Maximum tolerated concentration (MTC): The highest concentration that can cause serious poisoning in test animals, but all survive without any death within a certain period of time.
Minimum effective concentration (MEC): The minimum concentration of drug that can just cause an effect.
Bioavailability (F): The rate and amount of drug entering the blood circulation through non-intravenous injection routes, including absolute bioavailability and relative bioavailability.
Peak concentration, peak time and area under curve are important parameters for determining bioavailability and bioequivalence.
Parameters related to distribution process (D)
Apparent volume of distribution (Vd): It refers to the volume of body fluid required for the drug in the body to be distributed according to the blood drug concentration at this time when the blood plasma and tissue drug distribution reach equilibrium. Remember that this is only a theoretical concept. Vd is an imaginary volume and does not represent physiological volume. It represents the ratio of dosage to initial blood drug concentration (Co), unit: L/kg, generally between 0.04-20L/kg.
Significance: It can show the degree of drug binding with tissue. Vd is small, indicating that the drug is mainly distributed in plasma; Vd is large, indicating that the drug is mainly distributed in tissue.
Half-life (t1/2): It refers to the time required for the drug concentration or amount in the body to decrease by 50%, indicating the rate of drug metabolism or excretion in the body. The unit is min or h. It is used to guide the frequency of administration. In order to maintain the minimum effective concentration, the interval between administrations is roughly equal to half-life. About 5-6 half-lives, most of drugs are cleared from body.
Clearance rate (CL): It is volume of plasma cleared by body's clearance organs per unit time, that is, how much volume of plasma containing drugs is cleared by body per unit time. It is sum of all elimination organs' clearance rates for drugs in body (total clearance rate equals sum of individual clearance rates). Unit: mL/min or mL/(min.kg).
The liver blood flow rates of humans, dogs and rats are respectively: 25, 50 and 100 mL/(min.kg). If clearance rate is close to this value, it indicates that liver metabolism is very fast.
Parameters after multiple administrations
Steady-state plasma concentration (Css): With half-life as administration interval, continuous constant administration causes gradual accumulation of drugs in body. After 4-5 administrations, blood drug concentration basically reaches stable level. The blood drug concentration at this time is called steady-state blood drug concentration. Unit mg/L.
The time to reach steady-state blood drug concentration only depends on half-life and has nothing to do with dose, administration interval and administration route. However, dosage and administration interval can affect steady-state blood drug concentration. Large dose, high steady-state blood drug concentration; small dose, low steady-state blood drug concentration.
Loading dose: The first dose that can immediately reach or approach steady-state plasma concentration.
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