Pharmacokinetics One: Basic Pharmacokinetics:

“What the body does to the drug”

General:
Pharmacokinetics is thus the relationship between dose and the resulting plasma (or effect
site) concentration.

The following basic processes are involved in drug administration: (ADME)

 Absorption
 Distribution
 Metabolism
 Excretion

 these processes will determine the effect site concentration as well as the duration of
action of the drug.
 NB: Note that both metabolism and excretion, will contribute to elimination (ie
irreversible loss of drug from the body).
 Let’s look at these processes separately 

Absorption:

Describes the different routes for drugs to reach the (usually) vascular compartment. This
can be via the following:

 Oral
 Sublingual
 Rectal
 Applied to other epithelial surfaces (skin, cornea, vagina, nasal mucosa etc)
 Inhalation
 Injection: - subcutaneous
- intramuscular
- intraveneous
- intrathecal / epidural

 Bioavailability: Refers to the fraction of given dose that gains access to the systemic
circulation and is expressed as a percentage.
For orally administered dose = Area under [ ]-time curve (AUC) for
oral drug divided by the AUC for an IVI dose of that drug. (=assuming
that ivi administered dose gives 100% bioavailability).
Drugs with low bioavailability, might be those with extensive 1st - pass
metabolism or poorly absorbed drugs.

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  Bioinequivalence: Various formulations of same drug may yield different
bioavailabilities. Bioinequivalence is if there is a statistically significant difference.
 Therapeutic inequivalence: This is if there is a clinically significant difference
between bioavailabilities of different formulations of same drug.

 Most drugs are absorbed by simple diffusion, but some drugs are absorbed by active
transport ( eg L-dopa, alpha-methyldopa).

With simple diffusion, rate of transfer depends on the usual suspects: 1) Surface area
of absorption site, 2) lipid solubility of drug, 3) mw of drug (less NB than solubility) and
4) the blood supply to the site.
The solubility / tissue permeability for weak basic and acidic drugs depends on the degree
of ionization of the drug, which again depends on their own pKa + pH of environment.
(non-ionized drugs crosses lipid barriers better).
This can lead to so called pH-trapping: eg a weak acidic drug will tend to accumulate in
a compartment with relatively high pH ( = ionized form). E.g. Aspirin in an alkaline
urine…(forced alkaline diuresis used in mx of OD in the past).
Another practical example is the observation that LA’s (weak bases) are less effective
when injected in areas of tissue inflammation (  pH  more ionized drug less
effective to cross the neuronal lipid membrane).

 Methods for delaying absorption:

 Adding a vasoconstrictor ( eg adrenaline with local anaesthetics)

 Depot preparations of drugs: = relatively insoluble salts/esters/complexes of drugs
given sc or imi ( eg procaine penicillin = salt, medroxyprogesterone acetate =
ester = “depot provera” )
 Changing physical characteristics of a preparation: eg Insulin zinc suspensions
 Subcut implantation of solid pellets of the drug: eg estradiol.

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 Distribution

In general, the distribution of a drug in the body is related to the following:

 Plasma protein binding

 Lipid solubility of drug
 pKa of drug
 pH of body fluid
 Regional blood flow
 Specific drug properties (eg iodine uptake by the thyroid)/ extra-vascular binding
 Rapid central clearance (eg sux and remifentanil)

 Re: Plasma Protein Binding:

Most drugs exist mainly in bound form at therapeutic [ ]’s. It is however the free fraction that is
pharmacologically active.
Plasma albumin is the most important of the pl prot’s: it binds mainly acidic drugs (eg NSAIDS, warfarin
etc) and a small number of basic drugs ( eg TAD’s, chlorpromazine).
There are 2 binding sites per albumin molecule. These sites are non-specific and competition can occur
between different drugs. This is usually rare in practice as most drugs at therapeutic [ ]’ occupy only a
small fraction of binding sites (exception = sulphonamides for example, which occupy ~ 50% sites at
therapeutic [ ]‘s ). The Vd's of highly bound drugs (>90%) are the most affected by displacement as
well as changes in levels of plasma proteins.

Other pl proteins = beta globulin + alpha acid glycoprotein ( with inflammation, like
CRP) and tend to bind mainly basic drugs (eg opioids and LA's).

The amount of drug bound depends on: -1) [ ] of free drug , -2) [ ] of protein and
–3) affinity of drug for the binding sites.

Extensive protein binding influences distribution (retention of drug in plasma

compartment, -see below) + also elimination of the drug.

 Re: Lipid solubility / partitioning into body fat + other tissues:

Fat = large, non-polar compartment, however in practice this is NB only for a few drugs with a
sufficiently high enough fat:water partition coefficient.
E.g. Thiopentone (fat:water coefficient ~ 10 )  accumulates substantially in body fat. It is this
property that limits a single dose’s usage as an induction agent only (despite long
pharmacological half life).
Compare this to morphine, with a fat:water coefficient ~ 0.4  little partitioning into body fat.
Another factor limits accumulation of drugs in body fat: = the low blood supply of fatty tissue.( <
2% of CO ). So for practical purposes, partitioning into fat with drugs given acutely, = only
limited to a few highly lipid soluble drugs. With chronic dosing of lipid soluble drugs, fat
accumulation can be significant (eg benzodiazepines).

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Other tissues where drugs can accumulate:
- Retina (rich in melanin): eg chloroquine has high affinity for melanin
- Bones: eg Tetracyclines accumulate slowly in bones + teeth due to affinity for calcium.
- Amiodarone: - high affinity for liver, lung, thyroid + fat

 re: Compartmental distribution of drugs:

Keeping above in mind, drugs can thus be said to distribute in “compartments” in the
body. Obviously these compartments are theoretical, eg intracellular fluid compartment
comprises the intracellular fluid volumes of all the cells in the body etc.

 The major compartments with regard to drug distribution are:

- Plasma ~ 5% of total body weight (TBW)

- Interstitial fluid ~ 16% TBW
- Intracellular fluid ~ 35% TBW
- Transcellular fluid ~ 2% TBW
- Fat ~ 20% TBW

 The concept of Volume of distribution (VD):

Consider: CP = Q / VD and VD = Q / CP
Where:
CP = concentration of drug in the plasma
Q = total amount of drug in the whole body,
VD = apparent volume of distribution

Definition: The apparent volume of distribution is the volume of fluid required to contain
the total amount, Q, of drug in the body at the same concentration as that present in the
plasma, CP.

In other words, the volume of distribution is thus a proportionality factor that relates the amount
of drug in the body to the concentration of drug measured in a biological fluid (ie plasma). 

It is important that you grasp the concept that this is an apparent volume (thus, a drug
that distributes outside the plasma compartment would have a larger apparent VD than
one confined to the plasma only). Thus, while the volume may be similar to a physical
space in the body it is not necessary to assume that the apparent volume corresponds to a
physiological (or anatomical) volume.

Consider two examples:

- Drug A confined to plasma only: it is easy to grasp that VD = QA / CP
- Drug B distributes outside plasma: the thing to realize is that we take our sample to
measure the concentration, from the plasma (which of course will be diluted for
drug B c/f drug A)… The amount of drug is known, thus VD = QB / CP
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 Drugs confined to Plasma compartment:

Plasma volume ~ 0.05 l/kg body weight. Drugs that are confined to plasma should thus
have a VD fairly close to that of plasma volume. Drugs confined to plasma cmpt are
those that are either too large to cross capillary wall (eg Heparin) or those that are very
strongly plasma prot bound. (Remember however that it is the free drug in the interstitial
fluid that exerts effect…).
Evans blue is a dye that binds so strongly to pl albumin, that its VD is experimentally
used to measure plasma volume.

 Drugs distributed in ECF compartment:

Total ECF vol ~ 0.2 l/kg body weight. This is thus the approximate VD for many polar
drugs (doesn’t cross cell membranes, BBB or placenta) e.g. neuromuscular blockers,
gentamycin, carbenicillin.

 Drugs distributed throughout the body water:

Total body water ~ 0.55 l/kg. This approximates the VD of relatively lipid-soluble drugs
that easily cross cell membranes ( eg phenytoin).

 Note: Binding of drugs to tissues outside the plasma cmpt, or partitioning in fat,
increases VD beyond that of total body water… e.g. are morphine, TAD’s, haloperidol,
amiodarone, etc.

Finally: The total Vd of a drug is the sum total of the different compartmental Vd’s for
the specific drug.

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 Metabolism

As mentioned earlier, metabolism of a drug is one of the ways a drug is eliminated from
the body (the other is via excretion, eg renal, biliary, lungs etc).
Metabolism involves a change in the chemical structure of the drug, whereas with
excretion, the drug leaves the body unchanged.

As a general rule, most drugs leave the body in the urine: - either unchanged or as polar
metabolites. Lipophilic drugs are not eliminated efficiently by kidneys (diffuses back)
and have to be metabolized (liver) to more polar products (ie water soluble).

Drug metabolism occurs predominantly in liver, and especially via the cytochrome P450
system. Some of the P450 enzymes are extrahepatic ( eg in adrenals for steroid
synthesis).

Also note that the component stereoisomers in a drug that is given as a mixture of
stereoisomers, may undergo different metabolic pathways. Significant drug interactions
can occur by means of inhibition of metabolism between these stereoisomers.
(Isomerism is a BIG topic that will be dealt with in pharmaceutical aspects of drugs).

 Phases of hepatic metabolism:

Involves 2 kinds of biochemical reactions, phase 1 and phase 2 reactions, which occur
(usually) sequentially.
- Phase 1 reactions are catabolic (oxidation, reduction and hydrolysis)  products =
often more chemically reactive, and thus might be more toxic / carcinogenic than parent
compound. It usually introduces a reactive group, eg hydroxyl, into the compound,
which serves as a “point of attack” for ph 2 conjugation.

- Phase 2 reactions are anabolic and involve conjugation, with a glucuronide for
example, which usually yields inactive products (and polar).

These reactions occur usually in liver, but can occur elsewhere: - plasma (hydrolysis of
suxamethonium) , lung ( prostanoids) or in the gut ( tyramine, salbutamol).

The P450 enzymes (as with many other hepatic enzymes) are embedded in the smooth
ER, and thus known as “microsomal” enzymes.
To reach these enzymes, a drug thus needs to be relatively lipophilic (non-polar).

 Phase 1 reactions: Can be oxidative, reductive or hydrolytic. Most reactions are

oxidative and the P450 system the most important of the enzyme systems.
(Oxidation is the loss of electrons/hydrogen or addition of oxygen)

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 Notes on the P450 enzyme system:

- = Large family of related but distinct enzymes. (haem proteins)

- ~ 74 gene families isolated, 3 main ones in human liver = CYP1,2 and 3
- Different P450 enzymes have distinct, but often overlapping, substrate specificities.
- Examples of some drugs and their P450 isoenzymes:

P450 Isoenzyme Drug

CYP1A1 Theophylline
CYP1A2 paracetamol, tacrine, theophylline
CYP2 (8 families) enflurane, isoflurane, sevoflurane
CYP2C9 ibuprofen, phenytoin, warfarin
CYP2C19 omeprazole
CYP2D6* codeine, tramadol, metoprolol
CYP2E1 enflurane, halothane, alcohol
CYP3A4 fentanyl,alfentanil,sufentanil,methadone,midaz,
diazepam,triazolam,droperidol,lignocaine,bupiv,
ondansetron…

 Inhibition of P450:

- Inhibitors of P450 differ in their selectivity for the isoenzymes.

- Non-competitive inhibitors: ketoconazole (antifungal).

 Induction of microsomal enzymes:

Following drugs are examples of drugs that can, with chronic use, induce the microsomal
enzymes: Carbamazepine, phenytoin, ethanol, rifampicin, steroids
Enzyme induction can result in following:
-  Metabolism of drugs dependent on these enzymes for their metabolism (practical example
is the short duration of rocuronium in a patient on long term steroids etc)
-  or  drug toxicity: eg paracetamol’s toxicity is due to its ph 1 metabolites, and enzyme
induction will increase the risk of toxicity…

 Genetic polymorphism: Some of the above isoenzymes might be subject to genetically

determined polymorphism, notably CYP2D6, where increased or decreased metabolism of
codeine or tramadol may occur ("slow" vs "fast" acetylators)

 Other Phase 1 reactions:

- Alcohol dehydrogenase: Ethanol is metabolized by this cytosolic enzyme as well as CYP2E1
- Xanthine oxidase: metabolises mercaptopurine
- Monoamine oxidase: metabolizes many amines ( noradrenaline, tyramine, serotonine). MOA =
intracellular and found in neuronal + extraneuronal tissues.
- Hydrolytic reactions: occur in plasma + in many tissues (both ester + amide bonds can be
hydrolysed). Eg's: plasma-ChE, tissue esterases.
- Reductive reactions: warfarin (reduction is the gain of electrons/hydrogen)
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 Phase 2 reactions:

- Drugs (either the parent* drug or ph 1 metabolite) with a suitable “handle” ( eg

hydroxyl, thiol or amino group) are susceptible to conjugation. (= ph 2 reaction)
- The resulting conjugate is: - pharmacologically inactive (almost always)
- Polar (ie more water soluble)
- Excreted in urine or bile
- Glucuronyl is the group most often used for conjugation. Others are, sulfate,
methyl, glycyl, acetyl and glutathione.
- *Morphine is an example where parent drug undergoes ph-2 mainly (M6G + M3G).
- Several NB endogenous substances eg bilirubin + adrenal corticosteroids are also
conjugated by this system.
- Most ph 2 reactions occur in liver, but lung + kidney also involved.

 The concept of First Pass metabolism:

Liver (sometimes gut) extracts + metabolizes some drugs so efficiently that only small
amount of the absorbed drug reaches the circulation. = 1st pass metabolism.
This is a cause of low OBA.
It is NB for the following drugs: Aspirin, GTN, isosorbide, levodopa, lignocaine,
metoprolol, morphine ( OBA ~ 30%) , propranolol, salbutamol and verapamil.
First pass metabolism can be quite unpredictable and thus make oral dosing difficult for
some drugs.
Also, with drugs given PR, a percentage gets absorbed into the hepatic circulation and the
rest into the systemic circulation, thus bypassing liver 1st pass metabolism. So drugs
given PR have an extremely unpredictable bioavailability…

 Pharmacologically active metabolites:

 Prodrugs (inactive)  active metabolites (eg enalapril  enalaprilat; alpha methyldopa 

alpha methylnoradrenaline; Paracoxib...)
 Active parent drugs  active metabolites or toxic metabolites (eg Morphine  M6G;
tramadol  M1 metabolite, more active than tramadol at opioid receptors)
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Excretion

A) Renal:

Three fundamental renal processes involved: ( = nice review of basic renal processes  )

 Glomerular filtration
 Active tubular secretion
 Passive diffusion across the tubular epithelium (reabsorption).

Some drugs cleared almost completely on a single transit thru kidney ( eg penicillin) and
some are cleared extremely slowly ( eg diazepam). Most drugs however fall between
these extremes.

 Filtration:

Drugs with mw < 20 K = freely filtered. Large molecules eg heparin, are not. Also
albumin ( mw 68K) does not filter freely, thus highly bound drugs will have a lower [ ] in
the filtrate c/f total plasma [ ]. ( eg warfarin = 98% PPB, so [ ] in filtrate only 2% and
thus have a reduced clearance by filtration).

 Tubular secretion:

- 20% of renal plasma flow = filtered thru glomerulus, thus ~80% of drug passed on to
the peritubular capillaries of proximal tubule. Here, 2 non-selective transporters
exists: One for acidic drugs ( + various endogenous acids, eg uric acid) and one for
basic drugs.
- These carriers can transport drugs against an electrochemical gradient, and can thus
reduce pl [ ] to nearly zero.
- Since ~ 80% of drug presented to these transporters, it is potentially the most
effective mechanism of renal drug elimination.
- As opposed to filtration, clearance via secretion is not affected by pl prot binding.
(eg penicillin = ~ 80% PPB, but almost completely removed by prox tubular
secretion)
- Competition can occur for these transporters  drug interactions. Eg probenecid
actually used because of this property to prolong the duration of action of penicillin.
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 Diffusion across renal tubule:

- Water is reabsorbed as the glomerular filtrate moves along the tubule eventual
urine volume = only ~ 1% of the original filtrate.
- If tubule was freely permeable to drugs, ~ 99% drug will be passively reabsorbed
with water.
- Thus, drugs with high lipid solubility ( ie permeable to the tubule) are excreted
slowly because of this passive back diffusion.
- On the other hand, water soluble drugs (polar / low tubular permeability) remains in
the tubule after being filtered thru the glomerulus, and are thus very effectively
cleared. Eg = digoxin , aminoglycoside, some NDNMB’s
- Remember: Many drugs are either weak bases or weak acids and their degree of
ionization ( and thus tubular permeability) will change with changes in urinary pH.
This can lead to so called ion-trapping . Thus a weak base (eg morphine) will be
more rapidly excreted in an acidic urine and weak acids ( eg aspirin) more rapidly in
an alkaline urine ( in the past, forced alkaline diuresis in overdose).

B) Biliary excretion:

- Liver cells transport some drugs from plasma to bile via transport systems
similar to those of the renal tubule + which involve P-glycoprotein.
- Various hydrophilic drug conjugates ( esp glucuronides) = concentrated in
bile  delivered to intestine where glucuronide usually hydrolysed,
releasing active drug. Free drug can be reabsorbed + cycle thus repeated
( enterohepatic circulation). This can create a reservoir of drug + can
amount to 20% of total drug in body + prolongs drug duration.(eg
morphine)
- Several drugs undergo significant biliary excretion: Vecuronium and
rocuronium = excreted mainly unchanged in the bile.

Concept of Drug Clearance: (Cl)

By definition, Clearance is the volume of plasma that is cleared from a drug per unit time.
Units for clearance = vol/time. (eg ml/min).

Total drug clearance ( Cls) = sum of clearance due to hepatobiliary and renal
mechanisms.
The principles are the same as for eg creatinine clearance by the kidneys.

Note: It is important not to confuse clearance with rate of elimination (mg/min)…

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Short notes on Hepatic clearance (Clhep): (see texts for more detail)

 Based on Fick’s Principle: Vx = Qhep(Cax –Cvx) , where Vx = extraction of drug x by

liver (in mg/min), Qhep = liver flow and Cax and Cvx are the arterial and hepatic venous concentrations of
drug x.
 Now, Vx = Clhep x Cax (see pharmacokinetics-2)
 Thus: Clhep x Cax = Qhep(Cax –Cvx)

And: Clhep = Qhep x (Cax –Cvx)/Cax

And (Cax –Cvx)/Cax = also known as the hepatic extraction ratio (ER)

 Thus: Clhep = Qhep x ER

 For drugs with a high ER (>0.7), Clhep ~ Qhep .

This basically means that the intrinsic clearance (enzymatic capacity) is so high,
that the determining factor for Clhep is liver flow. Elimination is said to be flow or
perfusion limited for these drugs. Eg = propofol.

 For drugs with a low ER (<0.3), intrinsic clearance is low and in this case
changes in enzymatic activity (eg induction/inhibition) as well as changes in
protein binding will have a large effect on Clhep. In these cases liver flow does not
affect Clhep a lot. Elimination is now said to be capacity-limited or restrictive.
Eg = most barbiturates (eg Thiopentone), benzodiazepines, warfarin,
phenytoin…
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