Blood concentration curve

Because there is usually a critical concentration of a chemical in the blood that is necessary to elicit either a pharmacological or toxic effect, both the rate and extent of input or availability can alter the toxicity of a compound. In the majority of cases, the duration of effects will be a function of the length of time the blood-concentration curve is above the threshold concentration the intensity of the effect for many agents will be a function of the elevation of the blood-concentration curve above the threshold concentration. 

Blood AUC was determined from 0-7200 min time-blood concentration curve, corrected for the dose. 

Some drugs, such as ranitidine, cimetidine, and dipyridamole, after oral administration produce a blood concentration curve consisting of two peaks. This double-peak phenomenon is generally observed after the administration of a single dose to fasted patients. The rationale for the double-peak phenomenon has been attributed to variability in stomach emptying, variable intestinal motility, presence of food, enterohepatic recycling, or failure of a tablet... 

Phenytoin. Solid dispersions of phenytoin in PEG-4000,P l PEG-6000, and PVP were evaluated in vivo. The total areas under blood concentration curve (AUC) after oral administration to human volunteers were fourfold greater from a 1 10 PEG-4000 dispersion and 2.7-fold greater from a physical mixture than from phenytoin crystals. PEG-6000 dispersions (40% drug) were examined in mixed-breed dogs and compared with phenytoin sodium. Although phenytoin sodium dissolved several times faster in vitro than the solid dispersion of phenytoin, the two preparations were found to be bioequivalent. Sekikawa et al. " studied absorption of phenytoin in humans from PVP dispersions. The extent of bioavailability of phenytoin in phenytoin-PVP coprecipitate was 1.54 times greater than that of phenytoin alone. 

Fig. 1. Blood—drug concentration curve used to determine bioavailabiLitv and bioequivalence. C is the maximum dmg concentration in the blood and corresponds to some The AUC (shaded) represents the total amount of orally adininistered dmg the time from points A to B represents dmg onset, from points B to D, the duration MEC = minimum effective concentration MTC = minimum toxic concentration and TI = therapeutic index.

Delayed action soHd products are designed like conventional dosage forms to release all their dmg contents at one time, but only after a delayed period. Thus, the duration of action and the blood concentration—time curve is like that of a conventional product. However, the onset time is purposely designed to be long. 

Dtug interactions can cause serious problems in clinical practice especially when the affected dmg has the potential to be highly toxic. Furthermore, pharmacokinetic interactions are clinically important if the affected dmg has a narrow therapeutic range (i.e. small difference between the minimum effective concentration and the toxic concentration Fig. 1) and a steep concentration-response curve (i.e. significant alterations in pharmacological and/or adverse effects caused by small changes in blood concentration). 

Figure 19-6. Glucose tolerance test. Blood glucose curves of a normal and a diabetic individual after oral administration of 50 g of glucose. Note the initial raised concentration in the diabetic. A criterion of normality is the return of the curve to the initial value within 2 hours.

This model accurately predicted the time curves for blood concentration and urinary excretion of metabolites by male volunteers exposed to 100 ppm trichloroethylene (Sato et al. 1991). It was found that, while the amount of metabolite excretion increases with body weight, the concentration does not, because of a corresponding increase in urinary volume. Also, women and obese people, compared with slim men, have lower concentrations but longer residence times of blood trichloroethylene because of their higher fat content (Sato et al. 1991). As a consequence, the model predicted that 16 hours after exposure to trichloroethylene, one could expect a woman s blood level to be 30% higher and an obese man s level to be twofold higher than that of a slim man (Sato 1993). 

The answer is e. (Hardman, p 21J The fraction of a drug dose absorbed after oral administration is affected by a wide variety of factors that can strongly influence the peak blood levels and the time to peak blood concentration. The Vd and the total body clearance (Vd x first-order fte) also are important in determining the amount of drug that reaches the target tissue. Only the area under the blood concentration-time curve, however, reflects absorption, distribution, metabolism, and excretion factors it is the most reliable and popular method of evaluating bioavailability... 

AUC—area under the (blood concentration-time) curve AV—atr io ven t r icu lar p—beta... 

Validation of the model. The Perbellini model was validated using a data set for venous blood /7-hexane values in volunteers exposed for 4 hours (Veulemans et al. 1982). The range in the study was 334-368 g/L during exposure to 204 ppm the model predicted a value within this range. After 4 hours exposure to 102 ppm, the predicted value for venous blood -hexane concentration was about 10% below that actually observed in humans. The authors also compared their own data from previous studies on the correlation between venous blood -hexane concentrations and workplace concentrations. From the correlation curve, exposure at 102 ppm would predict a venous blood concentration of 176 g/L the model predicted 182 g/L. The urinary excretion rate of 2,5-hexanedione predicted by the model was also compared to a data set from 13 workers followed for 24 hours from the beginning of a workday. 

Noncompartmental analysis is limited in that it is not descriptive or predictive concentrations must be interpolated from data. The appeal of noncompartmental analysis is that the shape of the blood concentration-versus-time curve is not assumed to be represented by an exponential function and, therefore, estimates of metabolic and pharmacokinetic parameters are not biased by this assumption. In order to minimize errors in parameter estimates that are introduced by interpolation, a large number of data points that adequately define the concentration-versus-tie curve are needed. 

Hepatic elimination obeys exponential kinetics because metabolizing enzymes operate in the quasilinear region of their concentration-activity curve hence the amount of drug metabolized per unit of time diminishes with decreasing blood concentration. 

The blood concentration-time profile for a theoretical drug given extravascularly (e.g., orally) is shown in Figure 5.2. Some pharmacokinetic parameters, such as Cmax, T x> area under the curve, and half-life, can be estimated by visual inspection or computation from a con-... 

The elimination of [i C]triethanolamine from the blood of mice administered 1.0 mg/kg bw intravenously showed first-order biphasic kinetics with a rapid (0.58-h half-life) and a slow phase (10.2-h half-life). The slow phase half-lives for elimination of triethanolamine in mice after dermal exposure to 1000 and 2000 mg/kg bw in acetone were 9.7 h and 18.6 h. Skin absorption rates (as blood concentration-time curves) after dermal application of aqueous and neat [I CJtriethanolamine to mouse skin (2000 mg/kg bw, enclosed by a glass ring) showed no significant change with the use of water as the vehicle (Waechter Rick, 1988, cited in Knaak et al, 1997). 

Blood samples were taken at 0.25, 0.5, 1.5, 2.5, 4.5, 6.5, 8.5, 10.5 and 12.5 h and the concentration of theophylline in serum was assayed by a spectrophotometric method [7]. The samples were analysed in duplicate. Bioavailability was calculated from the area under the concentration curve following the trapezoidal rule. 

Fig. 2 shows the serum verapamil levels of each volunteer in both the fasted and the fed states, and the position of the majority of pellets at each blood sampling. Especially large differences in time-concentration curves were noted if in the fasted state the majority of pellets had already entered the intestine at 2 h but in the fed state remained in the stomach for more than 4 h... 

Clonidine is lipid-soluble and rapidly enters the brain from the circulation. Because of its relatively short half-life and the fact that its antihypertensive effect is directly related to blood concentration, oral clonidine must be given twice a day (or as a patch, below) to maintain smooth blood pressure control. However, as is not the case with methyldopa, the dose-response curve of clonidine is such that increasing doses are more effective (but also more toxic). 

Since benzodiazepines are metabolized by the cytochrome P450 family of isozymes,1 potential inhibitors of these may produce significant increases in blood concentrations of benzodiazepines. An example of this inhibition is the drug midazolam, administered as a presurgical anesthetic. Lam et al.11 reported a mean increase in the area under the curve of midazolam by ketoconazole (772%) and nefazodone (444%) in a group of 40 healthy human subjects administered 200 mg ketoconazole per day and 400 mg nefazodone per day. The authors concluded that caution should be exercised when use of midazolam is warranted with potent CYP3A4 inhibitors.11... 

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