Pharmacokinetics

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Introduction

Pharmacokinetics describes the concentrations of drug in the body over time

Mathematical representation is used to describe absorption, distribution, metabolism, and excretion

Related to effects of drugs on the body, or pharmacodynamics

Information is used to perform dosage calculations

 

 

 

Absorption

• requires passage across biological membranes
• majority of oral absorption occurs in the duodenum (large SA)
• affected by GI motility, blood flow (conc. gradient)metabolism and efflux, pH

passive diffusion

• most common
• rate depends on concentration, size, polarity, ionization

active transport

• not common
• requires energy and proteins; saturable
• effective for highly polar molecules (ie vitamin C)

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Bioavailability

 

Bioavailability is affected by the route of administration and must be factored into dose calculations

Major factors affecting bioavailability with oral drugs include:

• nature of drug formuation (stabilizers, binders, etc)
• chemical properties of drugs affecting absorption
• efflux from enterocytes
• first-pass metabolism in liver and intestine

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Drug Distribution

Reversible movement from blood to body tissues

Extent depends on:

• blood flow to given tissue
• ability of drug to transverse biological membranes
• degree of binding to blood proteins

Volume of Distribution

• apparent volume of fluid in which a drug is distributed
• assumes equal partioning throughout body; ie plasma concentration = that of rest of body
• as Vd remains contstant for a given drug, dose can be calculated to acheive a desired concentration

Vd = Q / Cp

• Vd = volume of distribution
• Q = total amount of drug in body
• Cp = plasma concentration

A large Vd implies retention in tissues outside of plasma, while a small Vd implies primary plasma retention

Some tissues have more/less affinity for a given agent

Binding to plasma proteins such as albumin reduces the amount of drug available, but acts as a reservoir

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Metabolism

metabolism of any given drug can vary up to 50-fold in a population, based on:

• diet and environment (ie smoking)
• genetic factors
• age
• sex
• disease

 

Phase I metabolism

• creating or unmasking of small polar/reactive groups, ie -OH, -SH, -NH₂
• cytochrome P450 (CYP) families 1,2,3responsible
  • broad substrate range; low individual specificity
  • expression varies amongst individuals
  • can be induced or inhibited by drugs and diet compounds
    • most common cause of ADRs

Phase II metabolism

conjugation of larger polar groups to small reactive functional groups, ie glucuronic acid, sulfate, glutathione, acetate

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Excretion

Elinimation half-life is independent of dose

Kidney is most important route for drug and metabolites, with active secretion taking place

• most water and lipophilic molecules are reabsorbed inloop of Henle
• polar compunds are not!
  • pH of urine can affect reabsorption

Liver: bile

Other:sweat, tears, reproductive fluids, milk, lung

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Clearance

• rate of elimination through metabolism and excretion
• t 1/2 = (0.693 x Vd) / Cl

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