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I M.PHARM (II Semester)

Dept. of Pharmaceutics




• Introduction
• Proteins and Peptides
• List of protein and peptide drugs
• Routes of administration
• Pharmacokinetics and pharmacodynamics of protein and peptide drugs
• References



• Recently the armamentarium (i.e., the medicines, equipment and techniques available to a medical
practitioner) pharmaceuticals almost completely comprised small organic molecules, the majority of
which were synthesized in the laboratory

• Steady advances in cellular biology and in biotechnology have allowed scientists to create new
therapeutic entities mimicking endogenous bioactive substances

• These new products include proteins, peptides, monoclonal antibodies, oligonucleotides, vaccines against
microbiological and non-microbiological diseases, and gene therapy treatments

• Pharmacists need to understand the pharmacokinetics and pharmacodynamics of these therapeutic
products of biotechnology, which will constitute an ever-increasing proportion of the medications that
thewywww.DuillolMbix.ecomcalled on to provide for patients.



• Proteins- are the large organic compounds made of amino acids arranged in a linear chain and
joined together by peptide bonds.

Protein > 50 amino acids
• Peptides- are short polymers formed from the linking in a defined order of amino acids.

Peptides< 50 amino acids
• The size range of these compounds that are in use ranges from 1 kDa to 320 kDa

• Smallest substance is oxytocin, a 9-amino-acid peptide which is produced by chemical synthesis

• Largest compound is the antihemophilic factor, a large glycoprotein produced by recombinant



Compound Molecular Volume of Elimination Administration Use
mass (kDa) distribution half life(h) (systemic

(Lkg−1) availability)

Becaplermin; Rh-platelet-derived growth factor (Regranex) 25 – – Topical gel Decubitus
(negligible) ulcer

Desmopressin (DDAVP, Stimate, Minirin) 1.18 – 1.5–2.5 Oral(0.0016);intra Synthetic
nasal (0.03) antidiuretic


DNase; dornase alfa (Pulmozyme) 29.3 Inhalation Breathing
(nebulizer) difficulty in
(negligible) cystic fibrosis

Coagulation factor VIIa (NovoSeven) 50 0.103 2.3 IV injection(1.0) Haemophilia

Insulin,w 5.8 0.26–0.36 True half SC(0.55–0.77) Diabetes



• Proteins and peptides of smaller size can only be administered orally. This is because large
peptides and proteins are subject to degradation and inactivation in the gastrointestinal tract.
There by systemic bioavailability will be negligible. Desmopressin (1.18 kDa)

• Becaplermin(25 kDa) is a drug that is administered topically as its site of action is on the surface
of the skin, even though there are no protein drugs that can be administered transdermally due
to their large molecular weight and thus interfering with systemic absorption.



• They can also be administered through nasal route, for example: DNase (Pulmozyme). It is an enzyme used to
break down thick mucus secretions in the respiratory tracts of cystic fibrosis patients. But for an inhaled protein
that requires systemic absorption in order to exert its therapeutic effect is the inhalable form of human insulin,
Exubera which have been showed better disposition and efficacy were comparable to those of subcutaneously
administered insulin and also its absorption was somewhat faster

• The majority of these drugs are administered parenterally, either subcutaneously, intramuscularly, or
systemically by intravenous injection or infusion
• Many of the drugs have very high systemic absorption from subcutaneous and intramuscular dosage forms.


Pharmacokinetics & Pharmacodynamics of Protein & Peptide drugs 8

• Apparent volumes of distribution of these proteins and peptides are relatively small and roughly
inversely correlated with their molecular weights

• However, irrespective of the value of the distribution volume, each protein is distributed to the
tissue containing receptors for its therapeutic activity in an amount adequate to elicit effect. This
specific distribution, though most important for effect, is often of too small a magnitude to affect
the value of the overall volume of distribution

• For proteins, the total volume of distribution at steady state is usually not more than twice the
initial volume of distribution
• Pegylation often decreases the volume of distribution of a protein drug.


Pharmacokinetics & Pharmacodynamics of Protein & Peptide drugs 9

• Most of the protein and peptide drugs have short elimination half lives, as recorded in
intravenous studies. However, when these drugs are administered by subcutaneous or
intramuscular injection, delayed absorption causes plasma drug levels to remain high for an
appreciable period of time

• Proteins and peptide drugs are glycosylated or pegylated to increase their half life

• The desired therapeutic and pharmacokinetics of these drugs can be achieved by bioengineering
such as by glycosylation, deglycosylation, pegylation, cyclization, or conjugation, etc.,

• The site and mechanism of elimination may be determined by charge, oil/water partition
cowewfwfi.DucloiMeixn.ctom, the presence of sugars or other functional groups associated with the protein and to
a large extent by molecular weight.


Pharmacokinetics & Pharmacodynamics of Protein & Peptide drugs 10

Elimination through kidney:
✓Proteins that are small enough to be filtered by the glomerulus in the kidney (<60 kDa) may either

be absorbed by endocytosis into proximal tubule cells followed by lysosomal degradation
(bradykinin) or may be metabolized by enzymes at the luminal brush border membrane

✓Proteins and peptides like insulin, parathyroid harmone and vasopressin are degraded by
peritubular receptors.

✓Receptor-mediated endocytosis in the kidney is also an important mechanism of degradation of
proteins that are too large to be filtered by the glomerulus


Pharmacokinetics & Pharmacodynamics of Protein & Peptide drugs 11

Degradation in liver by intracellular catabolism:
✓small polypepties (<1kDa): are transported to these cells by passive diffusion or carrier mediated


✓moderate size proteins (50-200kDa): receptor mediated endocytosis
Even though insulin has molecular weight of 5.8kDa, which is below the above mentioned range,
insulin is eliminated to a considerable extent by receptor-mediated endocytosis in the liver

✓largest proteins (200-400kDa): are opsonized by immunoglobulins followed by phagocytosis

✓prowtwewi.DnulocMiox.mcomplexes (>400kDa): eliminated by phagocytosis


Pharmacokinetics & Pharmacodynamics of Protein & Peptide drugs 12

• For certain proteins, elimination through receptor mediated endocytosis occurs outside the liver.
For example:
–Granulocyte colony stimulating factor (GCSF) binds to receptor in bone marrow that can
eliminate this protein by saturable process
–Macrophage colony stimulating factor (MCSF) is eliminated in part by binding to macrophages

• Elimination of these drugs may be complex process with dose-dependent, saturable


Pharmacokinetics & Pharmacodynamics of Protein & Peptide drugs 13

• Plasma levels of the protein drugs may infact, correlate poorly with therapeutic effect. The drug
may be cleared from blood not because of an elimination process but instead because it is taken
up by a receptor where it may reside for some time exerting its therapeutic effect

• The curve of therapeutic effect as a function of time may be temporarily displaced with respect
to the curve of plasma drug level over time, requiring the use of indirect PK and PD modelling



• Basic Pharmacokinetics. Sunil S Jambhekar and Philip J Breen.
Second edition 2012. Published:Pharmaceutical Press. Pg no.413-426.