Introduction
Pharmacokinetic is the kinesis (movement) of pharmacological substances (drugs) throughout the body, which includes all phases and processes from entering to leaving the body. It is merely “what the body does with the drug.” Those drug kinetics can be broadly divided into 4 (ADME):
- Absorption
- Distribution
- Metabolism
- Excretion
If the drug is administered intravenously, there are only three phases (DME) that do not include absorption. Pharmacokinetics involve transport of the drug across numerous biological membranes to reach its target site. Apart from traversing membrane barriers, the drug must to survive metabolism, mostly hepatic, and excretion (via the kidney, liver, and faeces).
A drug’s molecular size and structural properties, degree of ionization, relative lipid solubility of its ionized and nonionized forms, and binding to serum and tissue proteins are the factors that predict its transport and availability at sites of action.
Thus, pharmacokinetic characteristics determine the route(s) of administration, dose, duration of action, time of peak action, and frequency of administration of a drug.
Mechanisms of transport through biological membranes
- Diffusion – passive, facilitated
- Active Transport
- Vesicular transport – endocytosis, exocytosis
In passive transport, the drug molecule usually penetrates by diffusion along a concentration gradient by virtue of its solubility in the lipid bilayer.
Facilitated diffusion is a carrier-mediated transport process in which the driving force is simply the electrochemical gradient of the transported solute.
Active transport is characterized by a direct requirement for energy, capacity to move solute against an electrochemical gradient.
Paracellular Transport
Endothelium of capillaries and postcapillary venules have intercellular gaps adequately large to allow paracellular passage of solutes and fluid but that is generally limited by blood flow. Capillaries of the CNS and a variety of epithelial tissues have tight junctions (e.g. BBB, Placental barrier) that limit paracellular movement of drugs.
Absorption
Absorption is the movement of a drug from its site of administration into the systemic circulation.
The absorption is influenced by a number of variables, including the size of the drug molecules, ionization/pH, lipid solubility, food presence, vascularity, and surface area of the absorption site.
Bioavailability
A parameter bioavailability is employed to evaluate the extent of drug absorption. Bioavailability can be defined as fraction of administered drug reaches to the systemic circulation i.e. fractional quantity available for biological action. E.g. 100 mg of drug-X is administered orally and 70 mg reaches to the systemic circulation, then the bioavailability (F) for the drug-X is 0.7 (70%). It is 100% if drug-X is directly injected into systemic circulation (I.V. route).
First pass metabolism
Various drug in some extent metabolizes before reaching to the systemic circulation by liver/GIT, called 1st pass metabolism which further decreases bioavailability. it differs from usual metabolism which takes place after reaching to the systemic circulation.
Distribution
Distribution is the movement of drugs from systemic circulation to tissues/organs (target site)
The rate of delivery and quantity of drug distributed into tissues are influenced by tissue volume, capillary permeability, cardiac output, and regional blood flow. Most of the drug is initially delivered to the liver, kidney, brain, and other well-perfused organs. muscle, most viscera, skin, and fat receive the drug at a slower rate.
Redistribution
Redistribution is a phenomenon in which drug moves (distribute back) from its site of action into systemic circulation or other tissues/sites. This is the situation with the intravenous anaesthetic thiopental, a lipid-soluble drug. After being injected intravenously, thiopental quickly reaches its maximum concentration in the brain, because blood flow to the brain is high and thiopental readily crosses the BBB. The concentrations of thiopental then drop in the brain and plasma as it moves to other tissues like muscle and, at the end, fat tissue.
Apparent volume of distribution
The Apparent volume of distribution (V) represents the volume of bodily fluids assumed based on the concentration of the drug in the systemic circulation. Suppose drug X is given intravenously in an amount of 100 mg and the drug’s concentration in a blood sample is later determined to be 5 mg/L, the volume of distribution of drug X would be 20 L (100/5), meaning that drug X would be distributed throughout 20 L of bodily fluid volume (since the body is assumed to consist of a single homogenous fluid compartment). It indicates tissue deposition; a loading dosage is necessary to maintain the appropriate blood concentration; and hemodialysis is not advised in cases of drug poisoning with a high volume of distribution.
V = dose administered I.V. / plasma concentration
Plasma protein binding
Most drugs possess physicochemical affinity for plasma proteins and get reversibly bound to these. Acidic drugs generally bind to plasma albumin and basic drugs to α1 acid glycoprotein. Binding to albumin (which is more abundant) is quantitatively more important.
Drug with high plasma protein binding (PPB) have low volume of distribution as highly plasma protein bound drugs are largely restricted to the vascular compartment. The bound fraction is not available for action. However, it is in equilibrium with the free drug in plasma. It generally makes the drug long acting.
Metabolism
Metabolism is process of biotransformation of drugs and other xenobiotics into water soluble form, which is essential for their renal elimination from the body, as well as for termination of their biological activity.
Biotransformation reactions
(a) Nonsynthetic/ Functionalization/ Phase l reactions:
a functional group (-OH, -COOH, -CHO, -NH2, -SH) is generated or exposed, produces an active or inactive metabolite. These reactions are: –
- Oxidation
- Reduction
- Hydrolysis
- Cyclization
- Decyclization
A class of monooxygenases in the liver primarily catalyze oxidative reaction, which ultimately need a cytochrome P-450 haemoprotein. Understanding the clinically relevant substrate drugs, inhibitors, and inducers of the CYP isoenzymes is important because they are important for drug metabolism in humans and consequently responsible for various drug interactions
(b) Synthetic/Conjugation/ Phase II reactions:
an endogenous radical is conjugated to the drug-metabolite, making it primarily inactive except for a few drugs that are active, such as the sulfate conjugate of minoxidil and the glucuronide conjugate of morphine. These reactions are: –
- Acetylation
- Methylation
- Glucuronide conjugation
- Glutathione conjugation
- Glycine conjugation
- Sulfate conjugation
- Ribonucleoside/nucleotide synthesis
Certain drugs already have functional groups and are directly conjugated, while others undergo a phase I reaction first followed by a phase II reaction.
Rate of drug metabolism/elimination
First-order kinetics:
a constant fraction of drug is metabolized i.e. the amount of drug metabolized per unit time is proportional to the plasma concentration of the drug (Cp). Most drugs follow 1st order kinetics in their therapeutic concentration ranges.
Zero-order kinetics:
a constant amount of drug is metabolized per unit time. Some drugs, like ethanol and phenytoin, have metabolic capacity saturation at the commonly used concentrations.
Zero-order kinetics can also occur at high (toxic) concentrations as drug metabolizing capacity becomes saturated.
Excretion
Drugs are either eliminated unchanged or in the form of metabolites from the body. Understanding the drug’s kinetics of elimination serves as the basis for rational dosing regimens and allows for their adjustments according to individual needs. Drug elimination is the sumtotal of metabolic inactivation and excretion.
Clearance (CL)
The clearance of a drug is the theoretical volume of plasma from which the drug is completely removed in unit time. It can be calculated as:
CL = Rate of elimination/plasma conc. of drug (Cp)
Plasma half-life
The Plasma half-life (t½) of a drug is the time taken for its plasma concentration to be reduced to half of its original value. Although a drug’s complete elimination from the body can theoretically take an infinite time, but 4-5 half-lives is taken as the period to be eliminated completely from the body.
Renal Excretion
A drug may be excreted through the kidneys, liver, or feces. The kidney is the most important organ for excreting drugs and their metabolites. Renal excretion of unchanged drug is a major route of elimination for 25%–30% of drugs administered to humans. Excretion of drugs into sweat, saliva, and tears is quantitatively unimportant.
Three separate mechanisms are involved in the excretion of drugs and their metabolites in the urine: glomerular filtration, active tubular secretion, and passive tubular reabsorption. The amount of drug entering the tubular lumen by filtration depends on the glomerular filtration rate and the extent of plasma protein binding of the drug; only unbound drug is filtered.
The pH affects the passive reabsorption of weak electrolytes because the ionized forms of these substances are less permeable to the tubular cells. When the tubular urine is made more alkaline, weak acids are largely ionized and are excreted more rapidly and to a greater extent; conversely, acidification of the urine increases fractional ionization and excretion of weak basics. When treating drug poisoning, the urine can be appropriately alkalinized or acidified to speed up the elimination of drugs.
Drugs in milk secretion
Basic drugs may be slightly concentrated in milk because milk is more acidic than plasma; on the other hand, acidic drugs are less concentrated in milk than in plasma. Nonelectrolytes (e.g., ethanol and urea) readily enter breast milk and reach the same concentration as in plasma, independent of the pH of the milk.