PHARMACOKINETICS

Joseph De Soto MD, PhD, FAIC

Pharmacology

OVERVIEW Pharmacokinetics refers to what the body does to

a drug whereas pharmacodynamics refers to what a drug does to the body.

Pharmacokinetics can be broken down into 4 phases

ADME Absorption: the entry of the drug until it reaches the

blood Distribution: the movement of the drug to different

parts of the body via its movement through the blood Metabolism: the breakdown of the drug or

biotransformation of the drug Elimination: the removal of the drug and its

metabolites from the body

ROUTES OF ADMINISTRATION There are three major routes in which we can deliver

a medication these are 1. Enteral (GI tract) 2. Parenteral (injection) and 3. Topical (on the skin).

The route of administration is determined by the therapeutic objectives and the chemical physical properties of the medication.

ENTERAL Oral: These medications can be self administered.

When given in excess antidotes may be given such as activated charcoal. These medications will undergo first pass metabolism. In addition, the absorption rate can vary greatly between individuals.

Sublingual/buccal medications have the advantage of by- passing the liver and hence, avoiding first past metabolism.

Enteric coated medications are useful for limiting irritation to the stomach by some medications such as aspirin.

PARENTERAL IV injection (IV): is used often used when medications

cannot be absorbed orally. When using the IV route we bypass the absorption stage. The introduction of pathogens and delivering to much drug to fast are concerns. Drug cannot be overly lipid. There is also the “oops factor”

Intramuscular injection (IM): can be given in aqueous solution which is absorbed quickly or in depot form that is in a solution such as polyethylene glycol where the drug will slowly be absorbed.

Subcutaneous injection (SC): provides absorption through simple diffusion. This administers the medication slower than IV and slower than aqueous IM. Only small amounts of drug can be administered in this fashion.

ALTERNATIVE METHODS Rectal – administering a medication bypasses the

portal circulation by 50%. The choice is good if the drug might induce vomiting orally or if the patient is unconscious. Rectal absorption is often erratic.

Transdermal – is when a medication is given by a patch on the skin. This route is used often when a sustained release of a lipid soluble drug is needed. The rate of absorption may vary due to the skin characteristics.

Nasal inhalation – this route involves administration of drugs directly into the nose either for local need or small amounts of drug.

ABSORPTION OF DRUGS THROUGH THE GI TRACT

Absorption is the transfer of a drug from the site of administration to the bloodstream. Routes of administration other than intravenous may result in partial absorption of the drug and lower bioavailability.

There are 4 major mechanisms of absorption 1. Passive diffusion 2. Facilitated diffusion 3. Active transport and 4. Endocytosis/exocytosis.

PASSIVE DIFFUSION Most drugs are absorbed by passive diffusion. In this

process a drug must be able to pass through the cellular membrane.

When this situation is present drugs will pass from high to low down the concentration gradient.

Water soluble drugs may pass through aqueous channels present in the membrane , while lipid soluble molecules can pass directly through the membrane.

FACILITATED DIFFUSION & ACTIVE TRANSPORT

Larger drugs may have to pass through the cellular membrane through either facilitated diffusion or active transport.

Facilitated diffusion is a process where large protein channels can undergo conformational changes allowing the passage of specific drugs down their concentration gradient.

Active transport is a process where a large protein channel undergoes and conformational change utilizing energy to take specific drugs against the concentration gradient.

ENDOCYTOSIS AND EXOCYTOSIS

At times, a drug is so big that it can only be absorbed through endocytosis. In this process, the cell will engulf the drug via its cell membrane and transport the drug into the cell by pinching off the drug filled vesicle.

Exocytosis is when the drug is transported outside of the cell. The membrane of the vesicle containing the drug will merge with the membrane of the cellular membrane to release the drug to the exterior of the cell.

Both endo and exocytosis require the expenditure of energy.

EFFECT OF PH ON DRUG ABSORPTION

Drugs can most easily pass through most cellular membranes whether in or out when they have minimal charge. Protons because of their small size can cross membranes

Most drugs are either weak acids or weak bases.

Weak acid HA H+ + A- Pka = [H+][A]

[HA]

Weak base BH+ B + H+ Pka = [B][H+]

[BH+]

EFFECT OF PH ON DRUG ABSORPTION

When pH is less than pKa the protonated forms of HA and BH+ predominate. When pH is more than pKa the deprotonated forms of A- and B predominate.

At pH = pKa; [HA] = [A-] and [BH+] = [B]

In order to increase the amount of weak acid diffusion one must lower the pH.

In order to increase the amount of weak base diffusion one must increase the pH.

BLOOD FLOW AND SURFACE AREA

The more blood that flows to the GI tract or section thereof the greater the absorption. The greater the surface area the greater the absorption also.

Hence, for these reason drugs are more readily absorbed in the intestines than the stomach.

Regardless, it still takes time to absorb materials hence, when a person has diarrhea less amount of substance/drug is absorbed.

Conversely when we eat a meal gastric emptying is slowed and more drug is absorbed in the stomach.

P-GLYCOPROTEIN The P-glycoprotein is a fairly non-specific active

transporter that is found in the liver, kidneys, intestines, bile ducts, and brain capillaries.

This transporter evolved to get rid of harmful substances from intracellular compartments.

Increased intestinal expression of P-glycoprotein can reduce the absorption of drugs that are substrates for P-glycoprotein. Reducing bioavailability. (drug resistance)

On the other hand drug toxicity may result because

of decreased P-glycoprotein expression

BIOAVAILABILITY Assume a patient is given 10 mg of a pure drug

orally and 6 mg reach the patients blood stream. Then the bioavailability is 60%

By definition then if I give a patient drug A by IV the bioavailability is 100%.

Bioavailability is determined by comparing plasma levels of a drug given by one route as compared to the drug levels in the plasma when the drug is given IV.

DETERMINATION OF BIOAVAILABILITY

In general a plot of the plasma concentration of the drug vs time is made for when the drug is given IV an also by another route such as orally. The area under the curves are compared which gives the bioavailability.

FIRST-PASS HEPATIC METABOLISM

Among the most important factors that determines bioavailability is First-Pass metabolism. When a drug is taken orally it may begin being metabolized at the gut wall itself and the liver. First pass metabolism occurs primarily when a drug enters the portal system.

OTHER FACTORS IMPACTING BIOAVAILABILITY

Some drugs are chemically unstable in the presence of gastric acid or by the digestive enzymes found in the small intestines.

The solubility of the drug can also affect bioavailability. Hydrophilic drugs may not be able to diffuse across the gut and overly lipid soluble drugs may not be able to get to the surface of the gut.

The drugs that are absorbed most readily through the gut wall are mostly lipid soluble with some hydrophilic component.

DRUG DISTRIBUTION The reversible movement of a drug from the blood

stream into various portions of the extracellular fluid of the body is called distribution.

The drug distribution depends on cardiac output, local blood flow, capillary permeability, tissue volume, tissue components, and drug binding within the vascular compartment.

BLOOD FLOW & CAPILLARY PERMEABILITY

The rate of blood flow to different organs varies greatly. The more blood flow to an organ the more drug will flow to that organ. All other things being equal.

However , we have to consider the capillary permeability at the end organ especially for drugs that cannot pass through membranes via diffusion.

In the liver and spleen nearly any drug can pass into them while the brain due to the blood brain barrier only allows lipophilic drugs to enter with a few exceptions. Other organs are between the two in terms of availability for drug entry.

BINDING OF DRUGS TO PLASMA PROTEINS AND TISSUES

For a drug to be active it must be FREE. Our blood contains many proteins such as albumin, globulins, that bind many drugs. For the most part only a fraction of drugs are bound. This fraction is consistent.

The free drug concentration is maintained as a constant fraction of the total drug in the plasma.

Protein + drug ⇌ Protein-drug complex (Equilibrium)

Changes in the amount of protein in the blood can change this equilibrium.

PREFERENTIAL DISTRIBUTION Different tissues may have different proteins that

preferentially bind certain drugs resulting in a built of concentration of drug in a tissue type causing toxicity.

The type of transporter on the cell membranes will also cause excess of drug or analog to build up in tissues. For instance estrogen is 50x higher in breast tissue than in the plasma at equilibrium.

Lipid soluble drugs may disperse into fat, hence, very obese patients may have too much drug build up in fat tissue with inadequate amounts of drug at the target organ.

Again, the blood flow may also transport more drug to a certain organ. One reason the kidney is so susceptible to damage in the presence of several medications.

DISTRIBUTION INTO THE WATER COMPARTMENTS OF THE BODY

The body can be divided into three compartments: the plasma, interstitium, and intracellular areas.

We have about 4 L of fluid in our plasma. If a drug has a high molecular weight or is highly bound to plasma proteins most of it will tend to stay in the plasma.

The interstitium has about 10 L of fluid, drugs which are of low molecular weight but hydrophilic will tend to aggregate here.

The intracellular compartment has about 14 L of fluid and drugs of low molecular weight and lipophilic tend to aggregate here.

VOLUME OF DISTRIBUTION The apparent volume of distribution Vd is defined as

the fluid volume that is needed to contain the drug presented in the body initially when we first measured all the drug in the plasma.

Vd = Amount of drug/ Concentration

Or Concentration = Amount of drug/ Vd

Hence, we can calculate the Volume of distribution.The volume of distribution is usually not the same as the actual volume of the body fluid.

APPARENT VOLUME OF DISTRIBUTION

The Vd is often called the apparent volume of distribution as it frequently has no physiological or physical basis. A drug can usually be found associating to more than one compartment in the body in different degrees.

Additionally, the drug may not only bind to plasma components but to proteins, nucleic acids and lipids taking the drug out of circulation and increasing the apparent volume of distribution.

APPARENT VOLUME OF DISTRIBUTION

If the apparent volume of distribution may have little to do with the actual distribution volume why talk about it? Discussing the apparent volume of distribution helps us to understand drug distribution and can be used to help understand half life of a drug.

If the drug has a large Vd this indicates that a large fraction of the drug is outside the plasma and/or highly bound , remaining free from the excretory organs such as the kidney. Thus , the higher the Vd the slower the drug clearance.

DRUG CLEARANCE BY METABOLISM

Drugs can be cleared from the body by excretion and metabolism. The liver is most responsible for metabolic routes of clearance while the kidneys, biliary tact are responsible for most excretion with the lungs and skins playing secondary roles.

Clearance when first order can be approximated by the equation:

CL = 0.693 * (Vd /t1/2)t1/2 = 0.693 * (Vd/Cl)

t1/2 is the elimination half-life

KINETICS OF METABOLISM Drugs metabolism generally follows first order

kinetics when the drug concentration is low and zero order kinetics when drug concentration is high.

First order means that the rate of metabolism of drug metabolism is proportional to the amount of drug that is present.

Zero order refers to the constant rate of metabolism of a drug . This latter effect is generally due to saturation of the enzymes related to the particular metabolic process.

REACTIONS OF DRUG METABOLISM

The kidney has difficulty eliminating lipophilic drugs, hence lipophilic drugs are metabolized in the liver by Phase1 and Phase II reactions.

Phase I reactions involved the reduction, oxidation, or hydrolysis of the drug. A polar functional group is unmasked or introduced such as – OH and – NH2.

Phase II reactions consist of conjugation reactions. An endogenous substance such as glucuronic acid, sulfuric acid, acetic acid or an amino acid is added.

PHASE I REACTIONS Phase I reactions may increase, decrease or have no

effect on pharmacologic activity. If the phase I reaction or any other metabolic action activates a drug the original drug is called a prodrug.

Phase I reactions are controlled by the cytochrome p450 system. The p450 system also called the microsomal mixed function oxidases metabolize both endogenous and exogenous substances.

Let’s take CYP3A4, the 3 indicates the family, the A the subfamily and the 4 the isoenzyme type.

PHASE I REACTIONS There is a large amount of variability among racial

groups and among individuals within these groups. This can impact both the drugs efficacy and toxicity. This variability is often forgotten among clinicians as a one size fits all must be avoided.

Some medications can induce specific CYP enzymes. As an example St. Johns Wort can induce CYP3A4.

Some medications can inhibit through competitive inhibition or down regulation other specific CYP’s. Grape juice can inhibit CYP3A4.

PHASE II REACTIONS If a drug is hydrophilic enough after the phase I

reaction it ma be excreted through the kidney or bile. If not it can be conjugated. The most common type of conjugation is via glucuronic acid.

Medications that already have a –OH or NH2 may directly be conjugated. Sometimes a medication will undergo a phase II reactions prior to a phase I.

There is also some genetic variance with the enzymes involved with phase II reactions but not as much as we find in phaseI.

DRUG CLEARANCE BY THE KIDNEY

The kidney is the most important route excreting drugs. Drugs must have some degree of hydrophilic properties to be eliminated by the kidney.

Free drug NOT bound to albumin can pass from the glomerular capillary plexus into Bowman’s space. The glomerular filtration rate is about 125 ml/min in the average person.

DRUG CLEARANCE BY THE KIDNEY

Drugs may also be secreted from the capillary plexus surrounding the nephric lumen into the proximal tubule via active transport. There is a an active transporter for both weak acids and weak bases in the proximal tubule.

As a drug moves toward the distal convoluted tubule it will increase in concentration. Any lipid soluble drugs may now start to exit the distal tubule down its concentration gradient.

We can trap polarizable drugs in the lumen by increase the pH for weak acids and decreasing the pH for weak bases

DRUG CLEARANCE ALTERNATIVE ROUTES

Drug clearance also can occur via excretion through the intestines, bile, lungs, skin and breast milk during lactation.

Thus, total excretion approximates metabolism through the liver + excretion through the kidney, intestines, bile, lungs, skin, and breast milk.

Cltotal = Cl hep(met) + Clkid(exc) + Clintest,bile,lungs,skin,breat(exc)

DESIGN & OPTIMIZATION OF DOSAGE REGIMEN

Drugs may be given continuously via I.V. infusion or in a fixed dose periodic fashion as when medications are taken orally every 4 hours.

Continuous or repeated administration of medication results in drug accumulation until steady state occurs.

Steady state occurs when the rate of elimination equals the rate of drug administration.

CONTINUOUS INFUSION REGIMENS

During continuous drug infusion the rate of drug entry into the body is constant.

Assuming that the drug is eliminated via first order kinetics we can say that the rate of drug elimination increases proportionally as the drug concentration in the plasma increases.

At steady state the blood concentration of the drug is constant.

INFLUENCE OF RATE OF INFUSION ON STEADY STATE

The steady state plasma concentration is directly related proportional to the infusion rate. Thus, if the infusion rate is double the steady state concentration is doubled.

Any factor that decreases drug clearance increases the steady state concentration.

A faster infusion rate does not change the time needed to achieve steady state it only changes the concentration of steady state.

TIME REQUIRED TO REACH STEADY STATE

The rate constant for reaching the steady state is the same in magnitude as the rate constant for eliminating the drug. The half life of the drug (t1/2) is the time for half of the drug to be eliminated or when infused to reach half of the steady state concentration.

Thus, after 1, 2, 3, 4, and 5 and 6 t1/2 the percentage of the maximum steady state concentration with constant infusion is: 50%, 75%, 87.5%, 93.75%, and 96.8%. Steady state is considered to be reach at 4.5 t1/2

The t1/2 is what determines the time to steady state.

FIXED – DOSE/FIXED TIME REGIMENS Using fixed doses gives time dependent fluctuations

in the levels of circulating drug. In the case of repeated dosing of the drug the concentration of the drug oscillates about a mean.

When we give a drug orally only a fraction of the drug is given hence, the steady state concentration is reduced.

LOADING DOSE We may need to rapidly get to a certain plasma level

of drug in the case of sever infection or arrhythmias.

The loading dose is administered to get to the desired plasma levels quickly and is followed up by a maintenance dose.

The down side is that we increase the risk for toxicity.

How else can we rapidly reach a target blood concentration?

Use a drug with a shorter half life