Distribution

Pharmacokinetics
Distribution
Dr. S. Parasuraman
Associate Professor, Faculty of Pharmacy,
AIMST University, Malaysia.

Academic session: Mar. - Jul. 2022 (FoP) 2
Pharmacokinetics - distribution
• Drug distribution
reversibly leaves
is the process by which a drug
the bloodstreamand enters the
interstitium (extracellular fluid) and the tissues.
• Movement of drug proceeds until an equilibrium is
established between unbound drug in the plasma and
the tissue fluids.

• Apparent volume of distribution (V).
• Presuming that the body behaves as a single
homogeneous compartment with volume V into which
the drug gets immediately and uniformly distributed.

• Apparent volume of distribution (V).
Calculation:
• A 58 kg male patient is given 350 milligrams of Drug B,
which distributes throughout extracellular fluid, but not
readily into tissues. On measuring a peak level, we may
get a value of 20 milligrams per litter. Calculate the
apparent volume of distribution per Kg body weight.
= 350/20
= 17.5 litter of plasma
= 17.5/58
= 0.30 litter/ kg

• The distribution of a drug from the plasma to the
interstitium depends on
A. Cardiac output and local blood flow
B. capillary permeability
C. Binding of drugs to plasma proteins and tissues
D. Lipophilicity
E. Volume of distribution

Distribution of a drug depends on
A. Cardiac output and local blood flow
– The rate of blood flow to the tissue capillaries varies
widely.
– Blood flow to “vessel-rich organs” (brain, liver, and kidney)
is greater than that to the skeletal muscles.
– High blood flow, together with high lipophilicity permits
rapid distribution

B. Capillary permeability
– Capillary permeability is determined by capillary structure
and by the chemical nature of the drug. Capillary structure
varies in terms of the fraction of the basement membrane
exposed by slit junctions between endothelial cells.
– In the liver and spleen, a significant portion of the
basement
discontinuous capillaries through which large
membrane is exposed due to large,
plasma
proteins can pass. In the brain, the capillary structure is
continuous, and there are no slit junctions. To enter the
brain, drugs must pass through the endothelial cells of the
CNS capillaries or undergo active transport.

B. Capillary permeability

– Binding to plasma proteins: Reversible binding to plasma
proteins sequesters drugs in a nondiffusible form and
slows transfer out of the vascular compartment. Many
drugs reversibly bind to albumin, 1-acid glycoprotein, or
other proteins in plasma. Albumin is the major drug-
binding protein, and it may act as a drug reservoir. Drug
bound to albumin is not filtered by renal glomerulus but
may be cleared by the proximal renal tubule and liver.
– The extent of binding to proteins is dependent on several
factors such as affinity, number of binding sites, and drug
concentrations at the site.

– Binding to tissue proteins: Many drugs accumulate in
tissues, leading to higher concentrations in tissues than in
interstitial fluid and blood. Drugs may accumulate because
of binding to lipids, proteins, or nucleic acids. Drugs may
also undergo active transport into tissues. Tissue reservoirs
may serve as a major source of the drug and prolong its
actions or cause local drug toxicity.

D. Lipophilicity:
– The chemical nature of a drug strongly influences its ability
to cross cell membranes. Lipophilic drugs readily move
across most biologic membranes. By contrast, hydrophilic
drugs do not readily penetrate cell membranes and must
pass through slit junctions.

E. Volume of distribution
– The apparent volume of distribution (Vd) is defined as the
fluid volume that is required to contain the entire drug in
the body at the same concentration measured in the
plasma. It is calculated by dividing the dose that ultimately
gets into the systemic circulation by the plasma
concentration at time zero (C0).

Academic session: Sep. 2018 - Jan. 2019
(BPT)
13
E. Volume of distribution calculation:
• 64-year-old female patient (70 kg) was recently
diagnosed with gram-positive pathogenic infection. He
received 2000 mg of vancomycin as an IV loading dose.
The peak plasma concentration of vancomycin was
reported to be 28.5 mg/L. The apparent volume of
distribution is:
= Amount of drug/ Plasma concentration
= 2000/28.5
= 70.2 L for 70 kg
= 1 L/ kg

Academic session: Sep. 2018 - Jan. 2019
(BPT)
14

Distribution

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