What are the two main factors that affect the rate and absorption of an orally administered drug?

Many factors can influence the therapeutic efficacy of a drug, including pharmacokinetics, which refers to the passage of drugs into the body, through it, and out of the body.

Think of pharmacokinetics as a drug’s journey through the body, during which it passes through four different phases: absorption, distribution, metabolism, and excretion (ADME). The four steps are:

• Absorption: Describes how the drug moves from the site of administration to the site of action.
• Distribution: Describes the journey of the drug through the bloodstream to various tissues of the body.
• Metabolism: Describes the process that breaks down the drug.
• Excretion: Describes the removal of the drug from the body.

Let’s look at these phases in more detail:

Absorption

Absorption is the movement of a drug from its site of administration to the bloodstream. The rate and extent of drug absorption depend on multiple factors, such as:

• Route of administration
• The formulation and chemical properties of a drug
• Drug-food interactions

The administration (e.g., oral, intravenous, inhalation) of a drug influences bioavailability, the fraction of the active form of a drug that enters the bloodstream and successfully reaches its target site.

When a drug is given intravenously, absorption is not required, and bioavailability is 100% because the active form of the medicine is delivered immediately to the systemic circulation. However, orally administered medications have incomplete absorption and result in less drug delivery to the site of action. For example, many orally administered drugs are metabolized within the gut wall or the liver before reaching the systemic circulation. This is referred to as first-pass metabolism, which reduces drug absorption.

Distribution

The process of drug distribution is important because it can affect how much drug ends up in the active sites, and thus drug efficacy and toxicity. A drug will move from the absorption site to tissues around the body, such as brain tissue, fat, and muscle. Many factors could influence this, such as blood flow, lipophilicity, molecular size, and how the drug interacts with the components of blood, like plasma proteins.

For example, a drug like warfarin is highly protein-bound, which means only a small percentage of the drug is free in the bloodstream to exert its therapeutic effects. If a highly protein-bound drug is given in combination with warfarin, it could displace warfarin from the protein-binding site and increase the amount that enters the bloodstream.

Additionally, there are anatomical barriers found in certain organs like the blood-brain barrier, preventing certain drugs from going into brain tissue. Drugs with certain characteristics, like high lipophilicity, small size, and molecular weight will be better able to cross the blood brain barrier.

Metabolism

Cytochrome P450 (CYP450) enzymes are responsible for the biotransformation or metabolism of about 70-80% of all drugs in clinical use.

What are some factors that affect drug metabolism?

• Genetics can impact whether someone metabolizes drugs more quickly or slowly.
• Age can impact liver function; the elderly have reduced liver function and may metabolize drugs more slowly, increasing risk of intolerability, and newborns or infants have immature liver function and may require special dosing considerations.
• Drug interactions can lead to decreased drug metabolism by enzyme inhibition or increased drug metabolism by enzyme induction.

Generally, when a drug is metabolized through CYP450 enzymes, it results in inactive metabolites, which have none of the original drug’s pharmacologic activity. However, certain medications, like codeine, are inactive and become converted in the body into a pharmacologically active drug. These are commonly referred to as prodrugs.

As you can imagine, having genetic variations in CYP2D6, the metabolic pathway for codeine, can have significant clinical consequences. Usually, CYP2D6 poor metabolizers (PMs) have higher serum levels of active drugs. In codeine, PMs have higher serum levels of the inactive drug, which could result in inefficacy. Conversely, ultra-rapid metabolizers (UMs) will transform codeine to morphine extremely quickly, resulting in toxic morphine levels.

The FDA added a black box warning to the codeine drug label, stating that respiratory depression and death have occurred in children who received codeine following a tonsillectomy and/or adenoidectomy and who have evidence of being a CYP2D6 UM.

Excretion

Elimination involves both the metabolism and the excretion of the drug through the kidneys, and to a much smaller degree, into the bile.

Excretion into the urine through the kidneys is one of the most important mechanisms of drug removal.

Many factors affect excretion, such as:

• Direct renal dysfunction, which could prolong the half-life of certain drugs and necessitate dose adjustments.
• Age, which can contribute to differing rates of excretion and impact dosing of medications.
• Pathologies that impact renal blood flow, such as congestive heart failure and liver disease can make drug excretion less efficient

Whether it’s a patient who just had gastric bypass surgery, a CYP2D6 poor metabolizer, or a patient with renal dysfunction, an individual’s characteristics affect these four processes, which can ultimately influence medication selection.

In conclusion

The world of pharmacokinetics is vast, but understanding the basic mechanisms that govern the pharmacokinetics of a drug is vital to designing individualized treatment regimens for patients.

The Genomind PGx test report covers 9 pharmacokinetic genes that affect drug exposure and may inform drug dosage. Ask about pharmacokinetic genes during your next consultation!

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References

1. Sakai JB. Pharmacokinetics: The Absorption, Distribution, and Excretion of Drugs. In: Practical Pharmacology for the Pharmacy Technician. 2009:27-40.
2. Doogue MP. Polasek TM. The ABCD of clinical pharmacokinetics. Ther Adv Drug Saf. 2013;4(1):5-7.
3. Fender AC and Dobrev D. Bound to bleed: how altered albumin binding may dictate warfarin treatment outcome. Int J Cardiol Heart Vasc. 2019;22:214-215.
4. Banks WA. Characteristics of compounds that cross the blood-brain barrier. BMC Neurol. 2009;9(Suppl 1):S3.
5. Zanger UM. Schwab M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther. 2013;138(1):103-41.
6. Ortiz deMontellano PR. Cytochrome P450-activated prodrugs. Future Med Chem. 2013;5(2):213-228.

Drug absorption is a pharmacokinetic parameter that refers to the way a drug is absorbed from a pharmaceutical formulation into the bloodstream.

Image Credit: By NOOMEANG / Shutterstock

Several factors can affect the absorption of a drug into the body. These include:

• physicochemical properties (e.g. solubility)
• drug formulation (e.g. tablets, capsules, solutions)
• the route of administration (e.g. oral, buccal, sublingual, rectal, parenteral, topical, or inhaled)
• the rate of gastric emptying

The main pharmacokinetic parameters for absorption include:

• Absorption rate constant: absorption rate / amount of drug remaining to be absorbed
• Bioavailability: amount of drug absorbed / drug dose

A drug must be solubilized in order to cross the semipermeable cell membranes to reach the systemic circulation. These biological barriers exist to selectively allow or inhibit the passage of native and foreign particles through them.

Absorption Type: Passive Diffusion

Passive diffusion involves the crossing of a pharmaceutical substance across a cell membrane from an area of high drug concentration, such as  in the gastrointestinal tract,  to an area of low drug concentration, such as in  the blood.

This is a passive process that does not require energy, and the rate of diffusion is directly proportional to the concentration gradient. Other factors influencing passive diffusion include:

• the physicochemical properties of the drug, such as its:
  • lipid solubility
  • molecular size
  • degree of ionization
• the absorptive surface area available to the drug.

In general, lipid-soluble drugs, and drugs composed of smaller molecules, cross the cell membrane more easily and are more likely to be absorbed by passive diffusion.

As most drugs are weak acids or bases, they exist in the form of an equilibrium between the ionized and un-ionized form in an aqueous environment, such as the gastrointestinal tract. The un-ionized form usually diffuses across the cell membrane more readily as it is more lipophilic. The ionized form, on the other hand, exhibits high electrical resistance and is less likely to diffuse across the membrane. The ratio of the un-ionized form depends on the environmental pH and the acid dissociation constant (pKa).

Immediate-release products allow drugs to dissolve with no delay or prolonging dissolution or absorption of the drug. - Image Credit: PNOIARSA / Shutterstock

Absorption Type: Facilitated Passive Diffusion

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This refers to the passage of certain drugs across cell membranes according to the concentration gradient, but in association with specific substrate molecules which attach the drug molecule and diffuse across the membrane. This does not require energy.

Active transport requires energy to facilitate the transport of drug molecules against a concentration gradient, which usually occurs at specific sites in the small intestine.

The majority of drugs that are absorbed via active transport share a similar structure with endogenous substances such as ions, vitamins, sugars and amino acids.

Absorption Type: Pinocytosis

Pinocytosis involves absorption of fluid or particles following their encapsulation by a cell. The membrane of the cells closes in around the pharmacological substance and fuses to form a complete vesicle, which later detaches and moves into the inside of the cell. This process also requires energy to occur.

Standard and Controlled Release Oral Administration

When a drug is taken orally, it must be able to survive the low pH and presence of potentially degrading enzymes in the gastrointestinal tract before it can be absorbed into the bloodstream. Some peptide drugs such as insulin cannot be given orally for this reason.

There are some drug formulations that manipulate the properties of the drug to control the process of absorption. These are referred to as controlled-release medications. These changes limit the degree of fluctuation of the drug concentration, so that the rate of absorption is slowed down and extended over a longer period of time.  

Other Types of Administration (Non-Oral)

Drugs administered via intravenous (IV) injection or infusion do not need to be absorbed, as they are delivered directly into the bloodstream. However, there are several other types of non-oral administration routes that must be absorbed through cell membranes to reach the systemic circulation. These include buccal, sublingual, intramuscular, subcutaneous, rectal, topical, transdermal and inhaled.

Pharmacokinetics Drug Absorption Video

References

Further Reading

Last updated Jun 19, 2019