Absorption and first-pass effect
One of the most important issues in understanding bioavailability is how the anatomical features of venous drainage affect the fate of a drug. The key concept here is the first-pass effect through the liver.
When a drug is absorbed in the gastrointestinal tract, it does not always enter the general circulation directly. If the venous blood from the organ collects into the portal vein (v. portae), the substance inevitably passes through the liver, where it undergoes degradation (presystemic elimination). This significantly reduces the dose that ultimately reaches the target organs.
Anatomy of rectal administration
Drug administration via the rectum is characterized by a high rate of penetration into the systemic circulation. This is due to the unique structure of the vascular network in this region. Absorption is distributed between two basins:
- Lower and middle parts of the rectum: About half of the administered dose is absorbed here. Blood drains into the middle and lower rectal veins (vv. rectales mediae et inferiores), which empty directly into the inferior vena cava (v. cava inferior). Thus, the drug enters the systemic circulation, completely bypassing the liver and avoiding the first-pass effect.
- Upper part of the rectum: The remaining portion of the dose is absorbed here. Outflow proceeds via the superior rectal vein (v. rectalis superior), which carries blood into the portal vein (v. portae). This fraction of the drug is sent to the liver and undergoes presystemic elimination.
Elimination kinetics
Mathematical models are used to describe the processes of drug elimination. First-order kinetics is most commonly encountered in medical practice.
The main relationship in this model is the dependence between the drug's half-life and its elimination rate constant. It is expressed by a strict formula where the half-life equals the natural logarithm of the number 2 divided by the rate constant. In numerical terms, the natural logarithm of 2 is rounded to 0.693.
Briefly: answers to topical questions
Which routes of drug administration allow for avoiding the first-pass effect?
Sublingual administration and administration into the lower and middle parts of the rectum allow for avoiding the first-pass effect.
- Sublingually (sublingualis) — absorption into the systemic circulation, bypassing the liver.
- Lower and middle parts of the rectum — absorption occurs into the middle and inferior rectal veins (vv. rectales mediae et inferiores) bypassing the liver.
What types of elimination kinetics exist?
To reduce the concentration of medicinal substances, the following types of kinetics are distinguished:
- First-order kinetics — exponential, with a variable rate.
- Zero-order kinetics — linear, with a constant rate (saturable kinetics).
Which pharmacokinetic parameters describe the process of drug distribution?
The process of drug distribution in the body is described by such a parameter as the apparent volume of distribution.
- Apparent volume of distribution (apparent volume of distribution, $V_d$) — a hypothetical volume of fluid that would be required to dissolve the total amount of the substance so that its concentration equals that in the blood plasma.
Which organs are involved in the presystemic elimination of medicinal substances?
The following organs are involved in the process of presystemic elimination of drugs:
- Liver — the organ where presystemic metabolism and drug degradation occur.
- Intestinal wall — an extrahepatic site of metabolism, second in activity only to the liver.
- Kidneys — organs of extrahepatic metabolism.
How does first-order kinetics differ from zero-order kinetics?
The differences between the types of elimination kinetics lie in the nature of the rate change and its dependence on the concentration of the substance:
| Parameter | First-order kinetics | Zero-order kinetics |
|---|---|---|
| Nature of the rate | Variable rate, exponential | Constant rate, linear |
| Dose dependence | $t_{1/2}$ is constant, independent of dose | Depends on enzyme saturation |
| Graph | Exponential curve | Straight line |
Which parameters are necessary to calculate total drug clearance?
Pharmacokinetic parameters and indices of administration or elimination rate are used to calculate total drug clearance.
- Elimination rate — the amount of eliminated substance per unit of time.
- Concentration — the concentration of the substance in a biological fluid ($C$).
- Apparent volume of distribution ($V_d$) and elimination rate constant ($k_{el}$).
- Steady-state concentration ($C_{ss}$) and infusion rate during continuous infusion.
To remember rectal outflow: "Lowers go to the system, uppers go to the liver" (inferior veins to the inferior vena cava, superior vein to the portal vein).
Class and exam questions
What is the «first-pass» effect?
This is the process of presystemic elimination (metabolism) of a drug in the liver, which it enters via the portal vein system immediately after absorption, before reaching the general systemic circulation.
Why does rectal administration allow part of the drug to avoid destruction in the liver?
Because about 50% of the dose is absorbed in the lower and middle thirds of the rectum, from where blood drains into the inferior vena cava, bypassing the portal vein and the hepatic barrier.
How are the half-life and rate constant related in 1st-order kinetics?
They are inversely proportional. The half-life is calculated as 0.693 (the natural logarithm of two) divided by the elimination rate constant.
What else to study on this topic
- Mechanisms of presystemic elimination in the liver
- Features of rectal blood supply
- Calculation of drug half-life
- Differences between first- and zero-order kinetics
- Impact of the hepatic barrier on bioavailability
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