Drug Metabolism In Liver, Kidney , Intestine

And Placenta.

Bikash Kumar Sah

Principle of pharmacology and toxicology
M.pharm. 1st semester.
PUCMAS
Drug metabolism (Process of conversion of chemical forms of
substance.)

Essential pharmacokinetic process, that renders lipid soluble and non-

polar compound to water soluble and polar compounds. So that
easily excreted by various process.

Because only water soluble substance undergo excretion, whereas

lipid soluble substances are passively reabsorbed from renal or extra
renal excretory sites into blood by virtue of their lipophilicity.

Biotransformation(chemical transformation of xenobiotics in body

or living organism)
A series of enzyme catalyzed process that alters physiochemical
properties of foreign chemicals(drugs/xenobiotics) from those that
favors absorption across biological membrane (lipophilicity) to those
favouring elimination in urine and bile. (hydrophilicity).
Sites/organs of drug metabolism
PRIMARY ORGANS
The major sites of drug metabolism is liver.
(Microsomal enzymes system of hepatocytes)

SECONDARY ORGANS
Kidney (proximal tubule)
Lungs.
Intestine (enterocytes and intestinal microflora)
Placenta(trophoblast cells)
Testes (sertoli cells)
Skin (epithelial cells)
Drugs metabolizing enzyme
The metabolizing enzyme can be broadly classified into two types.
Microsomal enzymes
Non microsomal enzymes

Microsomal enzymes
The endoplasmic reticulum (especially smooth endoplasmic reticulum)
of liver and other tissues contain a large variety of enzymes,
together called microsomal enzymes.

They catalyse glucuronide conjugation, most oxidative reactions, and

some reductive and hydrolytic reactions.

The monooxygenases, glucuronyl transferase, etc are important

microsomal enzymes.
Non microsomal enzymes
Enzymes occurring in organelles/sites other than endoplasmic
reticulum (microsomes) are called non-microsomal enzymes.
These are usually present in the cytoplasm, mitochondria, etc. and
occur mainly in the liver, Gl tract, plasma and other tissues.
Liver metabolism in diseased condition

Acute liver impairment interferes with drug metabolism and

elimination.
Chronic liver impairment affects all parameters of pharmacokinetic.
Because most drugs are metabolized by the liver, it is susceptible to
drug toxicity.
Impaired liver function greatly increases the risks of adverse drug
effects.
General guidelines when using drugs include:
Clinical signs for hepatotoxicity should be sought (nausea, vomiting,
jaundice, hepatomegaly).
Hepatotoxic drugs should be avoided if possible: (acetaminophen,
INH, statins, methotrexate, phenytoin, aspirin and alcohol).
With cirrhosis, oral drugs are distributed directly into the systemic
circulation.
This means that oral drugs metabolized in the liver must be given in
reduced doses.
Effect of Hepatic Blood Flow in diseased state.
Hepatic metabolism also depends on hepatic blood flow. Hepatic blood
flow ↓ => delivery of drug to hepatocytes ↓ => drug metabolism ↓ =>
drug toxicity ↑.

Effect of protein binding in diseased state.

Protein binding affects distribution.
The impaired liver is unable to synthesize plasma proteins (albumin)
adequately.
Liver impairment causes accumulation of substances (bilirubin) that
displace drugs from protein-binding sites.
When protein binding ↓ => free drug ↑ => drug distribution to sites of
action & elimination ↑
=> onset of drug action ↑
=> duration of action ↓
When protein binding ↓ => peak blood levels and adverse effects ↑
Intestinal Metabolism.
In this type, drugs are metabolised in the gastrointestinal tract by
enzymes present in either gut mucosa or gut lumen before they are
absorbed .
Recent studies have indicated that P450 isoforms such as CYP2C19
and 3A4 in enterocytes might play an important role in the presystemic
intestinal metabolism of drugs and the large interindividual variability in
systemic exposure after oral administration .
Drug-metabolizing enzyme cytochrome P450 3A polypeptide
4(CYP3A4) in the human intestinal mucosa as well as the liver
contributes in a significant way to the first-pass metabolism of
intestinally dosed cyclosporine and midazolam.
The cytochrome P450 content of the intestine is about 35% of the
hepatic content in the rabbit, but accounts for only 4% of the hepatic
content in the mouse.
 Cytochrome P450 levels and activities are highest in the duodenum
near the pyrolus, and then decrease toward the colon .

A similar trend in regional activity levels along the intestine has been
observed for glucuronide, sulfate, and glutathione conjugating
enzymes.
In the gut mucosa, P-glycoprotein and cytochrome P450 (CYP)3A
functionally interact in three ways:
i) drugs are repeatedly taken up and pumped out of the enterocytes
by P-glycoprotein, thus increasing the probability of drugs being
metabolised.

ii) P-glycoprotein keeps intracellular drug concentrations within

the linear range of the metabolizing capacity of CYP3A.

iii) P-glycoprotein transports drug metabolites formed in the

mucosa back into the gut lumen.
Renal Metabolism
In addition to physiological functions of homeostasis in water and
electrolytes and the excretion of endogenous and exogenous
compounds from the body, the kidneys are the site of significant
biotransformation activities for both phase I and phase II metabolism.

The renal cortex, outer medulla, and inner medulla exhibit different
profiles of drug metabolism, which appears to be due to heterogeneous
distribution of metabolizing enzymes along the nephron.

Most metabolizing enzymes are localized mainly in the proximal

tubules, although various enzymes are distributed in all segments of the
nephron.
The pattern of renal blood flow, pH of the urine, and the urinary
concentrating mechanism can provide an environment that facilitates
the precipitation of certain compounds, including metabolites formed
within the kidneys.
 The pattern of renal blood flow, pH of the urine, and the urinary
concentrating mechanism can provide an environment that
facilitates the precipitation of certain compounds, including
metabolites formed within the kidneys.

The high concentration or crystallization of xenobiotics and/or

their metabolites can potentially cause significant renal impairment
in specific regions of the kidneys.
Placental metabolism
The major function of the placenta is to transfer nutrients and oxygen
from the mother to the foetus and to assist in the removal of waste
products from the foetus to the mother.
It plays an important role in the synthesis of hormones,peptides and
steroids that are vital for a successful pregnancy.
Acts as a barrier to protect the foetus from xenobiotics in the maternal
blood.
Nearly all drugs that are administered during pregnancy will enter, to
some degree,the circulation of the foetus (passive diffusion, active
transport, p-glycoprotein, facillated diffusion,
phagocytosis,pinocytosis.)
The extent to which drugs cross the placenta is also modulated by the
actions of placental phase I and II drug-metabolising enzymes,
which are present at levels that fluctuate throughout gestation.
 Cytochrome P450 (CYP) enzymes in particular have been well
characterized in the placenta at the level of mRNA, protein, and
enzyme activity. CYP1A1, 2E1, 3A4, 3A5, 3A7 and 4B1 have been
detected in the term placenta.
Placental xenobiotic-metabolising activities are altered in mothers
who abuse drugs, smoke, drink alcohol, are exposed to polluted air or
eat contaminated food.
While much less is known about phase II enzymes in the
placenta, some enzymes, in particular uridine diphosphate
glucuronosyltransferases, have been detected and shown to have
specific activity towards marker substrates, suggesting a significant role
of this enzyme in placental drug detoxification.
There is scant evidence in the literature for the presence of phase I
enzymes in the placenta other than cytochrome P450s (CYPs) and
growth of the foetus, when it is most susceptible to only a few phase II
enzymes have been well characterised.