Distribution is the process where the drug moves from the circulation
into different organs or tissues. While circulating in the blood plasma,
a drug typically alternates between its free form (unbound), and bound form, in which it binds to a
blood component such as albumin. Only the unbound form can move to other tissues.
Drug distribution to a particular tissue is determined by several factors, including:
- the rate of blood flow to the tissue, - the presence or absence of tissue factors
that can bind the drug, - and the ability of
the cells to take up the drug. To predict a drug’s behavior, simplifications
are made in which tissues and organs with similar drug distribution are grouped into compartments.
Drugs that remain largely in the circulation, or distribute mainly to their target organ,
are well described by one-compartment models. Drugs that distribute to multiple
organs and tissues are better explained with two-compartment or multi-compartment models.
A common model includes two compartments: a high-distribution central compartment consists
of blood plasma and highly perfused organs; and a low-distribution peripheral compartment that
includes less well perfused organs. The brain is an exception in most cases - it is well perfused
but the blood-brain barrier only allows certain types of molecules to pass through.
Within a compartment, the drug alternates between its bound and unbound forms. The
unbound form moves back and forth between compartments to maintain equilibrium.
Volume of distribution is an important indicator of the extent a drug is distributed
to body’s tissues. It is calculated as the amount of drug administered
divided by the concentration of the drug in blood plasma. For the same amount of drug given,
a large volume of distribution results when plasma concentration of the drug is low, which
usually indicates that the drug has mostly moved from the blood to body’s tissues. Conversely,
a small volume of distribution results from high plasma concentration,
meaning the drug remains largely in the blood, and has limited distribution to body’s tissues.
Volume of distribution indicates the extent of distribution from the blood,
but provides no information about the tissues into which the drug distributes. Two drugs
can have the same volume of distribution, but may distribute to different tissues.
The goal of drug metabolism is to chemically modify the drug so it can be eliminated from
the body. Specifically, a drug is metabolized to become more water-soluble to be excreted more
easily. There are several excretion pathways but most drugs are eliminated in urine or in bile,
with renal excretion being by far the most common. With age or kidney disease,
renal excretion decreases, resulting in reduced clearance rates for most drugs.
The major site of drug metabolism is the liver. Metabolism typically involves 2 phases:
non-synthetic, which may include oxidation, reduction, or hydrolysis;
and synthetic, which involves conjugation with an endogenous substance such as glucuronic
acid. Some drugs may undergo only one of the 2 phases. A number of liver enzymes
catalyze these reactions. The most important are phase-1 cytochrome P450 enzymes.
For most drugs used at therapeutic concentrations, the metabolism rate follows a so-called
“first-order” kinetics, meaning it is directly proportional to the amount of drug in the body.
In other words, the amount of drug metabolized per unit time is a constant fraction of the drug
remaining in the body. For example, if it takes 2 hours for the drug amount to be reduced by half,
from 1000 mg to 500 mg, it would take another 2 hours for the remaining 500 mg to be reduced
again by half, to 250 mg. This 2 hours’ time is known as the drug’s half-life.
However, at very high drug concentrations, when all metabolizing enzymes are working at
their maximum capacity, metabolism rate can no longer increase with drug concentration.
In this case, a fix amount of drug is metabolized per unit time
and drug clearance is said to follow zero-order kinetics.
Individual drug metabolism rates decrease with age and certain disorders such as liver diseases.
Other factors that can increase or decrease drug metabolism rates include:
- Genetic variations – some people have more active or less active
metabolizing enzymes than others; - And drug interactions. For example,
a number of medications and supplements, including herbal products, can stimulate or
inhibit cytochrome P450 activity, and therefore increasing or decreasing drug metabolism rates.
If a patient metabolizes a drug too slowly, drug concentration in the body may remain too high, and
regular drug doses may result in toxic effects. On the other hand, if a drug is metabolized too fast,
drug concentration may be too low to produce the desired therapeutic effects.
Metabolism underlies drug clearance mechanism, but for oral drugs, it occurs even before the
drugs can reach the systemic circulation. This is because after being absorbed in the intestines,
drugs are delivered directly to the liver via the portal system. This so-called “first-pass”
metabolism significantly reduces the amount of active drug reaching the systemic circulation
and must be taken into account when determining drug dosage. While first-pass metabolism typically
renders the drug inactive and therefore reduces bioavailability, some drugs are specifically
designed to take advantage of the process. Basically, they are produced in an inactive form,
called “pro-drug”, which becomes active only after being metabolized by the liver.