Plasma/blood drug concentration ratio

A microdialysis study was carried out to examine transport of oxycodone into the brain of rats [67], Oxycodone was administered by i.v. infusion, and unbound drug concentrations were monitored in both vena jugularis and striatum. Steady-state equilibrium was reached rapidly and drug levels in the two compartments declined in parallel at the end of the infusion. An unbound brain to unbound plasma ratio of 3.0 was measured which is 3- to 10-fold higher than for other opioids, and explains the similar in vivo potency of oxycodone in spite of lower receptor affinity. The authors interpret these data as de facto evidence of the existence of an as-yet unidentified transporter that carries oxycodone across the blood-brain barrier. 

As lithium is an alkaline earth metal which readily exchanges with sodium and potassium, it is actively transported across cell membranes. The penetration of kidney cells is particularly rapid, while that of bone, liver and brain tissue is much slower. The plasma CSE ratio in man has been calculated to be between 2 1 and 3 1, which is similar to that found for the plasma red blood cell (RBC) ratio. This suggests that the plasma RBC ratio might be a useful index of the brain concentration and may be predictive of the onset of side effects, as these appear to correlate well with the intracellular concentration of the drug. 

The use of microdialysis has enabled unbound drug concentrations to be determined in ECF, providing another measurement of penetration across the blood-brain barrier and one more closely related to activity. A review of data obtained by microdialysis [7], showed that free drug exposure in the brain is equal to or less than free drug concentration in plasma or blood, with ratios ranging from 4% for the most polar compound (atenolol) to unity for lipophilic compounds (e.g. carbamazepine). This largely supports the similar conclusions from the CSF data shown above. This relationship is illustrated in Figure 4.4. 

When a drug reaches the circulation, it quickly distributes outside the capillary beds into well-perfused tissues but may distribute slowly or not at all to less-accessible tissues protected by barriers, such as the brain. The volume of distribution is the ratio of the amount of drug in the body divided by the drug concentration in plasma once a pseudo-equilibrium is estabhshed between blood and tissues. For small molecules, a low volume of distribution generally signifies extensive plasma protein binding that restricts distribution outside the capillary bed, while a large volume of distribu-... 

Doses of 5 to 10 mg methamphetamine typically result in blood concentrations between 20 and 60 ng/ml. In one study,10 six healthy adults were orally administered a single dose of 0.125 mg/kg methamphetamine. Peak plasma concentrations were achieved at 3.6 h with a mean concentration of 20 ng/ml. In a second study, Lebish et al.11 observed a peak blood concentration of 30 ng/ml, 1 h after a single oral dose of 10 mg methamphetamine to one subject. In a study by Schepers et al.,12 eight subjects were administered four oral doses of 10 mg methamphetamine hydrochloride as sustained release tablets within 7 days. Three weeks later five subjects received four oral 20-mg doses. After the first dose, methamphetamine was detected in plasma between 0.25 and 2 h the cmax was 14.5 to 33.8 ng/ml (10-mg dose) and 26.2 to 44.3 ng/ml (20-mg) and occurred within 2 to 12 h. Methamphetamine was first detected in oral fluid in this study 0.08 to 2 h post dose, with a cmax of 24.7 to 312.2 and 75.3 to 321.7 ng/ml after the 10- and 20-mg doses, respectively. Peak methamphetamine concentrations in oral fluid occurred at 2 to 12 h and the median oral fluid-plasma concentration ratio was 2.0 for 24 h. In general, the detection window for drug in oral fluid exceeded that in plasma. 

Plasma versus Blood Clearance Calculation of Eh from drug clearance in blood requires the determination of chug concentration in whole blood. Since the determination of chug concentration is usually performed in plasma or serum, knowledge of the blood/plasma concentration ratio is necessary to estimate the blood clearance. Blood clearance is calculated using the equation... 

Blood is drawn as whole blood, that is, cells and plasma. Drug concentrations are measured in plasma, not whole blood. Whole blood is spun down in a centrifuge to allow separation of plasma from the cellular components. Plasma is more homogeneous than whole blood and therefore easier to analyze. The blood-to-plasma ratio of most drugs falls in a range of 0.5-1.5, and a value of 1 is generally not an unsafe assumption. In other words, the concentration of a drug in whole blood is often assumed to be the same as that... 

In case a concentration ratio (blood/plasma) is distinctly higher than the hematocrit value, this could indicate a binding of the drug or its metabolites to formed blood elements. 

It has been demonstrated that hepatic extraction ratio (ER) is also influenced by blood flow. A number of mathematical models have been proposed to explain this observation, but the simplest model, and the one that is easiest to apply to clinical practice, is the well stirred or venous equilibrium model (Equation 5.3). This model relates hepatic clearance to hepatic blood flow (Q), the fraction of drug concentration that is unbound in plasma (fu) and the intrinsic clearance of the unbound drug (Clyint) [1]. Intrinsic clearance represents the maximum clearance of drug in the absence of any restrictions caused by blood flow, binding or access to the metabolising enzymes. The model states that ... 

In addition to being distributed unevenly throu out the body, a drug may not be distributed evenly within tiie separate parts of a single tissue. In blood, drugs may tend to be concentrated either in the plasma or in the erythrocytes. Thus, it may prove to be of littie value to examine a plasma sample in a case where tiie drug involved is known to be concentrated in tiie erythrocytes (e.g. acetazol-amide). It is usual to examine whole blood in forensic cases whereas plasma is usually examined in clinical situations, and there could be a significant difference in the concentrations when measured in the two situations. The whole blood concentration and the plasma concentration cannot be compared until one or the otiier has been corrected by reference to the plasma whole blood ratio. 

Information about tiie extent of protein binding, and about tile plasma whole blood ratio provides an invaluable guide to the interpretation of drug concentiations in unfractionated blood samples. Using such data, total blood concentrations can be related to the unbound drug concentrations which are responsible for the observed condition. These data have been included, wherever possible, in the monographs in Part 2. 

Some authorities argue that it is improper to combine organ blood flow and -plasma concentrations in Equation 6.2 (7, 11). However/ in many cases the ratio of red cell/plasma drug concentrations remains constant over a wide concentration range so the same estimate of extraction ratio is obtained regardless of whether plasma concentrations or blood concentrations are measured. 

For a few drugs such as theophylline, saliva drug concentrations have been employed to supplement the collection of blood samples. However, the intersubject and intrasubject variability in saliva/plasma ratios have generally precluded the sole use of saliva drug concentrations to assess bioavailability. For some drugs such as cephalosporin antibiotics, clinical studies may also include a determination of appearance of drug in other body fluids such as the cerebrospinal fluid and bile. 

For enantiomeric drugs with low organ clearance, differences in renal or hepatic clearance between stereoisomers may reflect their free fraction in the plasma and not real stereoselectivity of the ability of the organ to remove the free enantiomers (intrinsic clearance) from the plasma. Clearance differences between stereoisomers of verapamil and disopyramide may be a function of plasma protein binding differences. In addition, volumes of distribution as well as concentration ratios of stereoisomers in body fluids to total plasma and blood are influenced by plasma protein binding. For example, the larger volume of distribution and greater total body clearance of R-disopyramide compared to the S isomer may be explained by the lower... 

The milk-to-plasma equilibrium concentration ratio of total (non-ionized plus ionized) drug is determined by the degree of ionization of the drug, which is pKa/pH-dependent, in blood and milk, the charge on... 

The unbound drug in the systemic circulation is available to distribute extravascularly. The extent of distribution is mainly determined by lipid solubility and, for weak organic acids and bases, is influenced by the pK3/pH-dependent degree of ionization because only the more lipid-soluble non-ionized form can passively diffuse through cell membranes and penetrate cellular barriers such as those which separate blood from transcellular fluids (cerebrospinal and synovial fluids and aqueous humour). The milk-to-plasma equilibrium concentration ratio of an antimicrobial agent provides a reasonably... 

Both the rate and extent of drug distribution across tissue barriers can have a profound impact on pharmacokinetic and pharmacodynamic properties. The extent of drug distribution manifests itself locally as the tissue to plasma (or blood) concentration ratio. Collectively, the extent of distribution into all the tissues results in the apparent volume of distribution. Simply put, the pharmacokinetic parameter volume of distribution reflects the ratio of individual tissue to plasma drug concentration weighed for tissue volume. The rate of distribution (together with the extent of distribution) can influence the shape of the plasma versus time profile for a drug, which can give rise to differences in elimination half-life as well as onset and duration of action. 

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