Area under concentration-time curve

There is no experimental evidence available to assess whether the toxicokinetics of -hexane differ between children and adults. Experiments in the rat model comparing kinetic parameters in weanling and mature animals after exposure to -hexane would be useful. These experiments should be designed to determine the concentration-time dependence (area under the curve) for blood levels of the neurotoxic /7-hcxane metabolite 2,5-hexanedione. w-Hcxanc and its metabolites cross the placenta in the rat (Bus et al. 1979) however, no preferential distribution to the fetus was observed. -Hexane has been detected, but not quantified, in human breast milk (Pellizzari et al. 1982), and a milk/blood partition coefficient of 2.10 has been determined experimentally in humans (Fisher et al. 1997). However, no pharmacokinetic experiments are available to confirm that -hexane or its metabolites are actually transferred to breast milk. Based on studies in humans, it appears unlikely that significant amounts of -hexane would be stored in human tissues at likely levels of exposure, so it is unlikely that maternal stores would be released upon pregnancy or lactation. A PBPK model is available for the transfer of M-hcxanc from milk to a nursing infant (Fisher et al. 1997) the model predicted that -hcxane intake by a nursing infant whose mother was exposed to 50 ppm at work would be well below the EPA advisory level for a 10-kg infant. However, this model cannot be validated without data on -hexane content in milk under known exposure conditions. 

In pharmaceutical research and drug development, noncompartmental analysis is normally the first and standard approach used to analyze pharmacokinetic data. The aim is to characterize the disposition of the drug in each individual, based on available concentration-time data. The assessment of pharmacokinetic parameters relies on a minimum set of assumptions, namely that drug elimination occurs exclusively from the sampling compartment, and that the drug follows linear pharmacokinetics that is, drug disposition is characterized by first-order processes (see Chapter 7). Calculations of pharmacokinetic parameters with this approach are usually based on statistical moments, namely the area under the concentration-time profile (area under the zero moment curve, AUC) and the area under the first moment curve (AUMC), as well as the terminal elimination rate constant (Xz) for extrapolation of AUC and AUMC beyond the measured data. Other pharmacokinetic parameters such as half-life (t1/2), clearance (CL), and volume of distribution (V) can then be derived. 

In 1950 French " and Wideqvist independently described a data treatment that makes use of the area under the concentration-time curve, and later authors have discussed the method.We introduce the technique by considering the second-order reaction of A and B, for which the differential rate equation is... 

Area under the Curve (AUC) refers to the area under the curve in a plasma concentration-time curve. It is directly proportional to the amount of drug which has appeared in the blood ( central compartment ), irrespective of the route of administration and the rate at which the drug enters. The bioavailability of an orally administered drug can be determined by comparing the AUCs following oral and intravenous administration. 

AUC is the area under the (diug) concentration time curve. 

Bioavailability is the amount of drug in a formulation that is released and becomes available for absorption or the amount of the drug absorbed after oral administration compared to the amount absorbed after intravenous administration (bioavailability - 100%), judged from areas remaining under plasma drug concentration-time curves. 

As the amount in the body decreases, the concentration decreases by the same law (-dC/d/ = Ke C), i.e., first-order kinetics resulting in an exponential function. The integral is the area under the concentration time curve (ACC). 

The concentration-time curve can be integrated numerically and yields the so-called area under the curve (AUC) ... 

The simplest non-compartmental parameter that can be obtained from the time course of the plasma concentration is its area under the curve AUC (see also Section 39.1.1) ... 

Compound (1) suffered from an unfavorable pharmacokinetic profile when studied in rats. It is cleared very rapidly from rat plasma (half-life, t 2 — 0.4/z) and is poorly bioavailable F — 2%), as reflected by the low plasma concentration (area under the plasma concentration-time curve, AUCo oo = 0.2pMh) following a single oral dose of 25mg/kg in rats [42]. The main challenge was to further optimize this series to obtain NS3 protease inhibitors with low-nanomolar cell-based potency (EC5q< 10 nM) and with an adequate pharmacokinetic profile for oral absorption. 

The area under the PCP concentration-time curve (AUC) from the time of antibody administration to the last measured concentration (Cn) was determined by the trapezoidal rule. The remaining area from Cn to time infinity was calculated by dividing Cn by the terminal elimination rate constant. By using dose, AUC, and the terminal elimination rate constant, we were able to calculate the terminal elimination half-life, systemic clearance, and the volume of distribution. Renal clearance was determined from the total amount of PCP appearing in the urine, divided by AUC. Unbound clearances were calculated based on unbound concentrations of PCP. The control values are from studies performed in our laboratory on dogs administered similar radioactive doses (i.e., 2.4 to 6.5 pg of PCP) (Woodworth et al., in press). Only one of the dogs (dog C) was used in both studies. 

When we calculated systemic and renal clearance based on the area under the unbound PCP concentration-time curve, we found essentially no change in these parameters compared to the control studies without antibody (Woodworth et al., in press) (figure 6). 

In studies in rats and mink that used more than one dose, the area under the plasma-IMPA concentration time curves indicated that at high doses the principal pathway for the conversion of diisopropyl methylphosphonate to IMPA was saturated (Bucci et al. 1992). In rats, metabolism was saturated at an oral dose of 660 mg/kg, but not at 66 mg/kg in mink, an oral dose of 270 mg/kg caused metabolic saturation which did not occur at 27 mg/kg. 

The significance of P-gp, however, in affecting absorption and bioavailability of P-gp substrate drugs can be seen in studies in knockout mice that do not have intestinal P-gp. The gene responsible for producing that protein has been knocked out of the genetic repertoire. Those animals evidenced a sixfold increase in plasma concentrations (and AUC, area under the plasma concentration-time curve) of the anticancer drug paclitaxel (Taxol) compared to the control animals [54]. Another line of evidence is the recent report... 

Table 2 Peak Plasma Levels and Areas Under Plasma Concentration Time Curves Following Oral and Intravenous Administration to Men...

AUMC = area under the first-moment curve for tissue i AUMCP = area under the first-moment curve for plasma AUCP = area under the plasma concentration-time curve... 

Area under the plasma concentration-time curve... 

Area under the (plasma concentration-time) curve... 

Daneshmend [104] measured the serum concentration of miconazole in 11 healthy adult females for 72 h following a single 1200 mg vaginal pessary. The mean peak serum miconazole concentration was 10.4 pg/L and the mean elimination half-life was 56.8 h. The mean area under the serum concentration-time curve was 967 pg/L/h. The calculated mean systemic bioavailability of the vaginal pessary was 1.4%. There was large intersubject variation in serum miconazole pharmacokinetics. This formulation may provide effective single dose treatment for vaginal candidiasis. 

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... 

Pharmacokinetic parameters such as area under the concentration-time curve (AUC) and maximal plasma concentration can be predictive of treatment outcome when specific ratios of AUC or maximal plasma concentration to the minimum inhibitory concentration (MIC) are achieved. For... 

In Eq. (3.4), doseiv is the amount of drug administered intravenously, AUC is total area under the drug concentration-time curve, and k is the first-order elimination rate constant... 

Exposure is represented by pharmacokinetic parameters demonstrating the local and systemic burden on the test species with the test compound and/or its metabolites. The area under the matrix level concentration-time curve (AUC) and/or the measurements of matrix concentrations at the expected peak-concentration time Cmax, or at some other selected time C(llme, are the most commonly used parameters. Other parameters might he more appropriate in particular cases. 

To take (e.g., 4 to 8) matrix samples during a dosing interval to make and estimate of Cmax and/or C(time) and area under matrix concentration time curve (AUC). 

Sampling Interval To be able to perform valid toxicokinetic analysis, it is not only necessary to properly collect samples of appropriate biological fluids, but also to collect a sufficient number of samples at the current intervals. Both of these variables are determined by the nature of the answers sought. Useful parameters in toxico-kinetic studies are Cmax, which is the peak plasma test compound concentration Tmax, which is the time at which the peak plasma test compound concentration occurs, Cmin, which is the plasma test compound concentration immediately before the next dose is administered AUC, which is the area under the plasma test compound concentration-time curve during a dosage interval, and t which is the half-life for the decline of test compound concentrations in plasma. The samples required to obtain these parameters are shown in Table 18.12. Cmin requires one blood sample immediately before a dose is given and provides information on accumulation. If there is no accumulation in plasma, the test compound may not be detected in this sample. 

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