Summary of Lecture I

DRUG METABOLISM

• Structural changes that occur to a foreign molecule (xenobiotic) in the body
• Drugs should have certain lipid solubility (lipophilic) to be absorbed.
• In the body will mostly be passively transferred into the tissues where they act on the receptors (active).
• If highly lipid soluble will not be eliminated form the body.
• To be excreted in the urine (major excretion site) a drug has to be polar enough to dissolve in water.
• Other excretion sites are sweat, saliva, bile etc…
• The introduction of small polar groups into the molecule (metabolism):
  A-ends pharmacological activity (alters fitting in the receptor) (Key & lock)
  B-ends toxicity (detoxification)
  C-increases polarity and water solubility (elimination).

Which fulfill the purpose of drug metabolism

• In general metabolism means detoxification
  Exceptions:

A-Inactive drug (mostly a pro-drug) by metabolism will produce active drug (bio-activation) e.g. prontosil.

B- metabolism of the activedrug (imipramine) gives the active metabolite (desipramine).
C-Some drugs give toxic metabolites e.g. chloarmphenicol.

Sites of drug metabolism

• divided into hepatic and extra hepatic:

1. Hepatic metabolism in the liver (major site of metabolism) for the following reasons:
   i- Rich in almost all drug-metabolizing enzymes
   ii-A well-perfused organ i.e easy access to the metabolizing enzymes.
   iii-Orally administered drugs will all pass through the liver before reaching systemic
   circulation thus extensively metabolised (first pass effect) the extent of metabolism may affect the bio-availability (Lidocain and nitroglycerine)
2. Extra hepatic metabolism: overall metabolism in tissues other than the liver.
   i-Intestine:
   a- estrases and lipases are abundant in intestinal wall leading to the hydrolysis of many ester pro-drugs.
   b-Intestinal b-glucuronidase enzyme hydrolyzes glucuronide conjugates the product will be reabsorbed into the blood stream (enterohepatic circulation or recycling) thus the drug stays longer in the body (affect duration of action).
   c- Bacterial flora present in the intestine and colon also contribute to the
   overall drug metabolism.
   ii-Kidney, lungs, adrenal glands, placenta, brain etc….

Figure 1 showing the fate of the drug in the body after administration

General pathways of drug metabolism

Phase I (Functionalization Reactions):

• Introduces a polar functional group e.g. OH, COOH, NH2, SH, into drug molecule
  a- direct introduction of the functional group (e.g. aromatic & aliphatic hydroxylation)
  b- modifying existing functionalities (e.g. reduction of ketones & aldehydes to alcohols, oxidation of alcohols to acids, hydrolysis of esters & amides to yield COOH, OH , NH groups, reduction of azo & nitro compounds to give NH2).
• Generally provides a functional group or handle in the molecule in preparation for phase II reactions.
• Product may be polar enough to be excreted.

Phase II (Conjugation Reactions):

• Attaches a small, polar& ionizable endogenous compounds such as glucuronic acid, sulfate, glycine and other amino acids to the functional group"handle" of phase I metabolites to produce water soluble conjugates.
• Conjugated metabolites are readily excreted in the urine and generally devoid of pharmacological activity and toxicity.
• Compounds with existing functional groups may go directly to phase II.
• Drugs which are already hydrophilic are largely excreted unchanged.

PHASE I (FUNCTIONALIZATION REACTIONS):

1-OXIDATION REACTIONS

• Requires molecular oxygen + reducing agent NADPH (reduced form of nicotinamide
  adenosine dinucleotide phosphate).

according to the following equation:

RH +NADPH+ O2+ H+ = ROH+ NADP+ +H2O

• The enzyme systems involved is called mixed function oxidases or monooxygenases. Composed of :
  a-Cytochrome P-450 (heme-protein). Transfers an oxygen atom to the substrate
  (RH) through the activation of molecular oxygen, introducing one oxygen atom into drug molecule & reduction of other to water
  b-NADPH- dependent cytochrome P-450 reductase.
  c- NADH- linked cytochrome b5.
  a + b + cofactors NADPH& NADH provide reducing equivalents (electrons).

• Cytochrome P450 is present in high concentration in liver. Also present in other tissues e.g kdney
• The name cytochrome P-450 is due to the reduced (Fe2+) form enzyme – substrate complex binding with carbon monoxide giving a complex with UV-absorption maximum at 450 nm.

Types of oxidation reactions catalyzed by Cytochrome P450

1-Oxidation of aromatic moieties (aromatic hydroxylation):

• Oxidation of aromatic compounds (arenes) by mixed function oxidase enzymes to phenolic metabolites (arenols) through epoxide intermediate (arene oxide).
• Arene oxides intermediates are extremely toxic, are highly electron deficient thus react with any nucleophils in the body.
• Body rids itself by detoxification pathways.
• Aromatic oxidation is a major pathway in human.

Scheme 1: Possible reaction pathways for the detoxification of arene oxid.

Rules for hydroxylation aromatic rings

Similar to electrophilic substitution rules:

• Para hydroxylation usually predominates (preferred) (less sterically hindered) e.g. phenobarbital.

e.g.phenobarbital

Sometimes ortho oxidation may take place.

• If two identical aromatic rings are present, oxidation of only one ring e.g.. phenybutazone

phenylbutazone

Chlorpromazine

• Substituents on aromatic ring influence the ease of hydroxylation. activated (electron rich) rings e.g. Diazepam arfe more susceptible.

Diazepam

Clonidine hydrochloride

• 4-2,3,7,6-tetrachlorodibenzo-p-dioxins (environmental pollutants) highly toxic: resistant to aromatic oxidation
• Resistance to metabolism + lipid solubility will lead to residance in the body.
  

2-Oxidation of olefins:

• Olefinic carbon–carbonwill produce epoxides (more stable than arene oxide)
• The epoxide is susceptible to enzymatic hydration by epoxide hydras giving the1, 2- dihydrodiols.

example is the oxidation of chlorpromazine (above) into diole metabolite through the stable active epoxide intermediate which contributes to the overall activity of the drug.

also the oxidation of alcofenac side chain to the diol metabolite (above).
simillarly secobarbital is metabolized to diol metabolite through the formation of the epoxide.

• Epoxide intermediate is very toxic and is highly electron deficient will attack nucleophils in surrounding enzymeleading to covalent bonding to the enzyme and its destruction (suicidal complex). Thus causing inhibition of the enzyme and prolong duration.

3- Oxidation at benzyllic carbon atoms:

• Carbon atoms attached to aromatic rings (benzyllic) oxidation produces alcohols (carbinol) ) metabolite.
• Primary alcohols metabolites are further oxidized to aldehydes and carboxylic acids (CH2OH→CHO→COOH). Eg. tolbutamide.

4- Oxidation at allylic carbon atoms:

• Commonly observed in drug metabolism

Tolbutamide........................................ THC

more preferable, less

sterically hindered

metabolically active site.

5-Oxidation at carbon atoms alpha to carbonyl and imines:
benzodiazepines an important class of drugs undergo oxidation to 3-hydroxyl metabolite

6-Oxidation at aliphatic and alicyclic carbon atoms:

• Oxidation at the terminal carbon (ω – oxidation)
• ω -1 also called penultimate carbon atom (carbon next to the last carbon)
• The alcohol metabolites undergoes further oxidation giving aldehydes and ketones or carboxylic acid. e.g. anticonvulsant valproic acid

valproic acid

secobarbital

Phenylbutazone