The phenomenon and rationale of marked dependence of drug concentration on blood sampling site. Implications in pharmacokinetics, pharmacodynamics, toxicology and therapeutics (Part I).

At least 42 compounds have been reported to exhibit significant or marked blood sampling site dependence in concentration after dosing in humans and animals. The very high efficiency of uptake of drug by the poorly perfused sampling tissue (e.g. arm or leg) during its very short transit through the capillary (1 to 3 seconds) is mainly responsible for such a universal phenomenon. When marked arteriovenous concentration differences exist, their entire plasma (blood or serum) concentration-time profiles may resemble those obtained from completely different drugs or from different dosing rates. After an intravenous bolus injection, the reported maximal arteriovenous differences were 3240-fold for griseofulvin during the early distribution phase (arterial concentration being higher than venous, and 234% for procainamide during the terminal phase (venous concentration being higher). The reported maximal steady-state arteriovenous difference during infusion was 3.8-fold for glyceryl trinitrate (nitroglycerin), with the arterial level higher, due to metabolism and possible strong binding by sampling tissue. Interestingly, peak arterial plasma concentrations were usually achieved at about 0.5 minutes, while peak venous plasma concentrations generally occurred at 1 to 5 minutes after injection. Thus, the plasma concentration-time profile after an intravenous bolus injection actually resembles that predicted for a short term intravenous infusion, according to the classical instantaneous input hypothesis. Potential factors that may affect the degree of arteriovenous difference are here reviewed in detail. The implications of potential marked arteriovenous differences in pharmacokinetics, in pharmacokinetic/pharmacodynamic correlations or modelling, in toxicology, and in drug therapy are extensively discussed. Clinicians or scientists dealing with the determination and/or use of plasma concentration data should be fully aware of this problem. Many previous studies, based on the commonly accepted assumption that immediately or shortly after dosing plasma (blood) concentrations are essentially uniform throughout the blood circulation or the central (plasma) compartment, may require a reexamination. This is particularly important since the 'driving force' for distribution of a drug to various parts of the body for elimination, for accumulation or for producing a pharmacological or toxic effect, is its concentration in arterial blood, and not in venous blood drained from a poorly perfused tissue (venous blood may more accurately reflect drug concentrations in the poorly perfused sampling tissue itself). The present review probably represents the first of its kind ever reported in the literature. It is hoped that the review will increase the awareness of this very fundamental and important subject matter among our readers, and may also stimulate further studies or discussions.