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LO: Pharmacokinetic (Questions 1-5)
1. Understand the concept of prodrugs and relate the duration of effect of different
drugs to their metabolism and the presence of biologically active metabolites
Prodrugs: inactive precursors that are metabolized to active metabolites, that is, the parent
compound, which is first ingested (or injected etc.), lacks activity of its own. These are
sometimes designed deliberately to overcome problems of drug delivery and to maximize
bioavailability of oral ingestion.
Examples include azathioprine, which is metabolized to mercaptopurine (an
immunosuppressant drug) and enalapril, an angiotensin-converting enzyme inhibitor is
hydrolysed to its active form, enalaprilat. Aspirin is also a prodrug of salicylic acid.
Drug Metabolism
Before excretion of drugs through the urine (and sometimes in the faeces, sweat or breast milk),
most drugs undergo metabolism in the liver (and sometimes in the lungs, plasma or gut).
Metabolism of drugs is the enzymatic conversion of one chemical entity to another for the
following purposes;
 To terminate the drug action (except in some phase 1 reactions)
 Allow for elimination of the drug by have polar/charged group to molecules in order to
make them more water soluble in the preparation for excretion
This metabolism involves 2 types of biochemical reactions;
 Phase 1 reactions are catabolic (eg. Oxidation, reduction or hydrolysis) and the products
are often more chemically reactive and therefore can sometimes be more carcinogenic
or toxic than the parent drug
 Phase 2 reactions are synthetic and involve conjugation, which results in the more
inactive molecules
Molecules can undergo just phase 1 or just phase 2, but most undergo both.
Obviously, the longer that a drug molecule is in the systemic circulation in it’s’ bioavailable form,
the more effective (or toxic) it is. Therefore, in the instances where there is presystemic
metabolism in the liver of the gut wall, the bioavailability of the drug is greatly reduced (hence
why some drugs will be administered IV instead of orally – eg. Morphine).
This is known as first pass metabolism and is a problem due to;
 A much larger dose of the drug is needed orally than when administered via other
routes
 There are marked individual variations in the first pass metabolism of a drug, therefore
there is an element of unpredictability
2. Outline how the metabolism and/or excretion of a drug may be influenced by the
physicochemical properties of the drug
Metabolism
If a drug is polar, it is less-readily able to cross a plasma membrane than the non-polar
molecules and therefore is unable to reach the metabolizing enzymes in the liver. Therefore,
intracellular metabolism is in general less important for polar drugs than for lipid soluble drugs
and the former tend to be excreted unchanged in the urine. Non-polar drugs can readily access
the intracellular enzymes, but are eliminated very inefficiently due to passive tubular
reabsorption (hence why the 2 stage metabolism is the most normal path).
Excretion
 In order for a drug to be excreted in the urine, it must by hydrophilic, whereas most
drugs on administration is lipophilic (which enables them to cross cell membranes)
 Ionized drugs (which are filtered during glomerular filtration in the kidney) undergo little
reabsorption and are excreted
 Lipophilic or non-ionised drugs that enter the kidney will be reabsorbed back into the
interstitial fluid (and may undergo another circuit of the system) and are therefore not
eliminated or they undergo passive tubular reabsorption back into the urine, but this
process requires a lot of energy and is largely inefficient
 Drugs bound to plasma proteins (most commonly albumin) cannot filter, but can
sometimes dissociate and then undergo tubular secretion for excretion in the urine.
The effect of pH
 Urinary acidification accelerates excretion of weak bases and retards that of weak acids
 Urinary alkalinisation has the opposite effect – it reduces excretion of weak bases and
increases the excretion of weak acids
 Increasing plasma pH causes weakly acidic drugs to be extracted from the CNS into the
plasma. The opposite is also true – by decreasing the plasma pH, weakly acidic drugs will
become concentrated in the CNS, increasing their neurotoxicity
3. Describe the basic mechanisms of Phase I and Phase II reactions and how they
influence the excretion of drugs
Sorry… may have gone a little OTT with this one.
Phase 1 reactions often introduce a reactive group, such as a
hydroxyl into the molecule (termed ‘functionalisation’). This
point later serves as the ‘point of attack’ to which the
conjugating system in phase 2 can attach the glucuronide
The P450 Monooxygenase System
 Cytochrome P450 enzymes are heame proteins,
comprising a large family of related but distinct
enzymes.
 These enzymes differ in amino acid sequence,
sensitivity to inhibitors and inducing agents and
specificity of reactions. Some members have
overlapping substrate specificities, with some enzymes acting on the same substrate but
at different rates
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Drug oxidation by the monooxygenase P450 system requires the following;
o Drug
o P450 enzyme
o Molecular oxygen
o NADPH
o Flavoprotein
The mechanism is somewhat complex, but the result is the addition of one atom of
oxygen to the drug to form the hydroxyl group (product ‘DOH’)
Bottom line: Cytochrome P450 enzymes have unique redox properties that are
fundamental to their diverse functions.
Important to note that there are large variations in the expression and regulation of
P450 enzymes between species and environmental factors are also important – eg.
Grapefruit juice inhibits drug metabolism
Other Phase 1 Reactions
 Not all drug oxidation reactions involve the P450 system. Examples include;
o Ethanol is metabolized by soluble cytoplasmic enzyme, alcohol dehydrogenase,
in addition to CYP2E1 (part of the P450 system)
o 6-mercaptopurine is oxidized by xanthine oxidase
o Monoamine oxidase inactivates many biologically active amines (eg.
Noradrenaline)
 Reductive reactions also take place (although are apparently less important). Eg.
Warfarin is inactivated by conversion of ketone to a hydroxyl group
 Hydrolytic reactions (eg. In aspirin) do not involve hepatic enzymes, but do occur in
plasma and many tissues.
Phase 2 deals with drugs that have a suitable ‘handle’ (ie. A hydroxyl, thiol or amino group),
either in the parent or as a result of a phase 1 reaction and conjugates them in order to prepare
for excretion.
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The groups that are added most often involve glucuronyl, sulfate, methyl, acetyl and
glycyl. Glucuronide formation involves the formation of a high-energy phosphate
compound, uridine diphosphate (UDP) glucaronic acid, from which glucuronic acid is
transferred to an electron-rich atom (N, O or S) on the substrate, forming an amide,
ester or thiol bond
Acetylation and methylation reactions occur with acetyl-CoA and S-adenosyl methionine
respectively, acting as the donor compounds
Many of the conjugation reactions occur in the liver, but other tissues (such as the lung
or kidney) are also involved
The resulting conjugate is almost always pharmacologically inactive and less lipid-soluble than
its precursor and is excreted in bile or urine.
4. Outline the mechanisms involved in renal and biliary elimination of drugs
Renal Excretion
3 fundamental processes account for renal drug excretion;
 Glomerular filtration
o Most drugs can cross the glomerular capillary barrier freely (except those bound
to albumin and heparin)
o Up to 20% of renal plasma flow is filtered through the glomerulus
 Active tubular secretion
o Approximately 80% of the delivered drug pass onto the peritubular capillaries of
the proximal tubule and transferred to the tubular lumen by two independent
and relatively non-selective carrier systems (one transports acidic drugs, whilst
the other handles organic bases)
o These carriers can carry molecules against an electrochemical gradient and can
therefore reduced plasma concentration to almost 0
o This is the most effective renal drug elimination system as can actively transport
protein bound molecules
 Passive diffusion across tubular epithelium
o If the tubule is freely permeable to drug molecules, roughly 99% of the filtered
drug will by reabsorbed passively, therefore this is where lipid-soluble drugs will
go back into circulation, whereas the polar hydrophilic drugs will continue in the
tubule to excretion
Biliary Elimination
Please refer to question 5 below.
5.
Describe how enterohepatic recirculation prolongs the duration of action of drugs
Various hydrophilic drug conjugates are concentrates in bile and delivered to the intestine,
where glucuronide is usually hydrolysed, releasing the active drug once more, which then can be
reabsorbed and the cycle repeated – this is termed enterohepatic circulation – the effect of this
is to create a ‘reservoir’ of recirculating drug that can amount to 20% of total drug in the body
and this prolongs the drug’s action. This is important for morphine, aspirin, chloramphenicole
(an antibiotic) and digoxin (inotrophic agent).
In the event that gut bacteria hydrolyses the drug, resulting in deacetylation (such as Rifampicin),
the drug will not be reabsorbed and will not undergo enterohepatic recirculation. It is then
passed out in the faeces.