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Introduction
Book Chapter 1
Lecture Outline ADME and ADME processes Routes of Administration Amounts in Plasma Pharmacokinetic Models Rate Processes and Constants
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Pharmacolkinetics: Definition
What is Pharmacokinetics?
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Pharmacolkinetics: Definition
Even if a drug has the best efficacy at its receptor, it will only work well if it reaches its target (the place where it should act) with the right concentration and with the right timing and duration Pharmacokinetics deals with concentration of a drug in a central compartment (blood, plasma) after administration of a drug dose(s). The aim to characterize the kinetic processes (= rate processes) of an administered dose(s) of drugs
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Pharmacolkinetics: ADME
Pharmacokinetics deals with the drugs ADME: - Absorption )( - Distribution )( - Metabolism - Excretion )(
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Pharmacolkinetics: ADME
Absorption: is the process by which the drug proceeds from the site of administration to the site of measurement (usually plasma, serum or blood) Distribution: the reversible transfer of the drug from the site of measurement (to muscle tissue, fat etc.) Metabolism: the chemical conversion to other (mostly inactive) molecules Excretion: the irreversible loss of drug from the body in the unchanged form
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Pharmacolkinetics: ADME
Two other important terms are related to ADME: Elimination )(: irreversible loss of drug from the site of measurement due to metabolism + excretion Disposition )(: the processes of distribution and elimination overlap can not always be separated. Disposition is loss of drug from the site of action due to distribution + elimination
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Pharmacolkinetics: ADME
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Routes of Administration
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Amounts in Plasma
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Pharmacokinetic Models
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Linear Pharmacokinetics
Most ADME processes have equation containing the term ex or e-x So ADME processes are typically first order processes This suggests that they occur mostly by passive diffusion Therefore, the processes (e.g. elimination) are directly proportional to the dose administered If this proportionality exists we say that the pharmacokinetics (PK) is linear
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Compartments Concept
Because ADME processes are very complex, we must simplify This is done by assuming ) (a compartment model The body is described as 1, 2, 3 or more compartments )( More compartments more complex models
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Compartments Concept
Usually, blood and well-perfused organs (lungs, kidneys, liver) are pooled in one compartment com. 1 = central compartment Other parts: fat tissue, bone, cartilage are comp. 2 peripheral tissue compartment Choice of model depends on the drug distribution Fast (immediate) equilibrium between central and other compartments one compartment model Equilibrium at time significantly >0 two compartment model
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Because there are two phases: absorption and elimination we also need a bi-exponential equation
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Where:
(Xa)t=0 is the amount of drug that can be absorbed (absorbable amount) Ka is the first order absorption rate const. K is the first order elimination rate const. X0 is administered dose, F is the absorbable fraction V is the distribution volume
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Measurable Quantities
We can not measure absorption, distribution and metabolism directly We can measure the blood levels in time and the excretion in urine (and feces) of the parent (unchanged) drug and its metabolites Mass balance considerations dictate that at time t - For intravascular route: Dose = amount in body + amount metabolized + cumulative amount excreted (unchanged)
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Y = Y0 - K0t
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