Area under curve pharmacokinetics, oral

The pharmacokinetic properties of AR-A014418 have been studied in Sprague-Dawley rats. After per oral dosing of 1 p.mol/kg of AR-A014418, the maximal total concentration (Cmax) in plasma was 3.75 p.M with an area under curve (AUC) of 22.4 p.M h and the half-life was determined to be 8.7 h with a Tmax of 0.26 h. After an i.v. bolus dose of 3 p.mol/kg, followed by an infusion of 3 p.mol/kg/h over 2 h to obtain a steady state between plasma and... 

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 pharmacokinetic information that can be obtained from the first study in man is dependent on the route of administration. When a drug is given intravenously, its bioavailabihty is 100%, and clearance and volume of distribution can be obtained in addition to half-life. Over a range of doses it can be established whether the area under the plasma concentration-time curve (AUC) increases in proportion to the dose and hence whether the kinetic parameters are independent of dose (see Figure 4.1). When a drug is administered orally, the half-life can still be determined, but only the apparent volume of distribution and clearance can be calculated because bioavailability is unknown. However, if the maximum concentration (Cmax) and AUC increase proportionately with dose, and the half-life is constant, it can usually be assumed that clearance is independent of dose. If, on the other hand, the AUC does not increase in proportion to the dose, this could be the result of a change in bioavailability, clearance or both. 

So the major difference between the two curves is attributable to drug absorption in the oral dosing experiment. The extent of that difference can be measured by comparing the area under each of the curves (there are several mathematical ways of doing this, which can be found in textbooks of pharmacokinetics if you are interested in pursuing this). 

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-... 

Phagocytosis rate increase. Polysaccharide fraction of the fruit, administered to adults at a concentration of 10 pg/mL, was active on polymorphonuclear leukocytes k Pharmacokinetics. Hexane extract of the fruit, administered rectally to 12 healthy male adults at a dose of 640 mg, produced bioavailability similar to that observed for the oral formulations. Extract, administered orally to healthy males at a dose of 320 mg (1 X 320 mg capsule, new formulation or 2 X 160 mg, reference preparation) for 1 month, produced a rapid absorption with a peak time (T J of 1.5-1.58 hour and peak plasma level (C J of 2.54-2.67 pg/mL. The area under the curve value ranged from 7.99 to 8.42 pg/hour/mL. The plasma concentration-time profile of both preparation was nearly identical. Both preparations can be considered as bioequivalenp Hexane ex-... 

Rectal bioavailability and pharmacokinetics. Serenoa repens extract, administered rectally to 12 healthy male volunteers at a dose of 640 mg/person, produced the mean maximum concentration in plasma of nearly 2.60 (Xg/mL approx 3 hours after administration, with mean value for the area under the curve AUC 10 (Xg/hour/mL. The bioavailability and pharmacokinetic profile were similar to those observed after oral administration. T j occurred approx 1 hour later, and plasma concentration 8 hours after drug administration was still quantified. The drug tolerability was good, and no adverse effect was observed ". Serenoa repens capsules, administered orally at a dose of 160 mg four times daily or rectally 640 mg daily for 30 days to 60 patients with BPH, produced no significant differences in diminu-... 

Kita et al. [154] have undertaken a study to help predict the optimal dosage of omeprazole for extensive metabolizers in the anti-H. pylori therapy. Seven healthy Japanese subjects, classified based on the CYP2C19 genotype into extensive metabolizers (n = 4) and poor metabolizers (ft = 3), participated in this study. Each subject received a single oral dose of omeprazole 20, 40, and 80 mg, with at least a 1-week washout period between each dose. Plasma concentrations of omeprazole and its two metabolites were monitored for 12 h after each dose of medication. After each dose was administered, the pharmacokinetic profiles of omeprazole and its two metabolites were significantly different between extensive metabolizers and poor metabolizers. The area under the plasma concentration-time curve of omeprazole in extensive metabolziers was disproportionally increased 3.2- or 19.2-fold with dose escalation from 20 to 40 to 80 mg omeprazole, respectively. In contrast, the area under the plasma concentration-time curve of omeprazole was proportionally increased with the higher dose in poor metabolizers. The area under the plasma concentration-time curve of omeprazole after 20 mg administration to poor metabolizers was almost equal to the area under the plasma concentration-time curve in extensive metabolizers after 80 mg administration. The recommended dose of omeprazole for extensive metabolizers is a maximum of 80 mg x 2/day based on pharmacokinetic considerations. 

To date, only one study has evaluated the pharmacokinetics of the alkamides contained in the Echinacea products administered to humans (27). Subjects (n - 11) received a single oral 2.5-mL dose of the 60% ethanolic extract from E. angustifolia roots or placebo (60% ethanol). Six different alkamides were analyzed (1) Undeca-2D/Z-ene-8,10-diynoic acid isobutylamides (2) Dodeca-2D,4Z-diene-8,10-diynoic acidisobutylamide (3) Dodeca-2E-ene-8,10-diynoic acid isobutylamide (4) Dodeca-2E,4E,8Z,10E/ Z-tetraenoic acid isobutylamides (5) Dodeca-2E,4E,8Z-trienoic acid isobutylamide and (6) Dodeca-2E,4E-dienoic acid isobutylamide. The extract contained approx 2.5 mg of (4), and approx 0.5 mg of all other components. The Cmax and area under the curve (AUC) for (4) were approx 10-fold that achieved with each of the other components. Thus, despite a fivefold higher amount per dose, the 10-fold greater Cmax and AUC achieved with (4) suggest it exhibits a greater bioavailability than the other components. 

Diltiazem was shown to exhibit dose dependent (30 mg - 120 mg administrated orally, three times a day) nonlinear pharmacokinetics (43) when administered to healthy individuals. The nonlinearity of diltiazem area under the curve (AUC) is a result of dose dependent first pass metabolism and is not reflected in the elimination half-life which is the same regardless of dose. The mean apparent oral clearance (44) and half-life of diltiazem following chronic oral therapy was 20.9 mL/min/kg and 3.5 hours, respectively. After a constant rate infusion, diltiazem was also shown to exhibit (45) nonlinear pharmacokinetics. After IV administration the following pharmacokinetic parameters were determined in healthy male volunteers the elimination t-1/2 (40) was 11.2 hours and the total clearance was 11.5 mL/min/kg. Diltiazem elimination is affected by liver damage (46) but not by kidney failure. 

Plasma area under the concentration—time curves (AUCs) of 57 NCEs were determined following oral cassette administration (5—9 NCEs/cassette) to mice. Physicochemical properties [such as, molecular weight, calculated molar refractivity, and calculated lipophilicity (clogP)] and molecular descriptors [such as presence or absence of N-methylation, cyclobutyl moiety, or heteroatoms (non-C,H,0,N)] were calculated or estimated for these compounds. This structural data, along with the corresponding pharmacokinetic parameters (primarily AUC), were used to develop artificial neural network models [8]. These models were used to predict the AUCs of compounds under synthesis [10]. This approach demonstrates that predictive models could be developed which potentially predict in vivo pharmacokinetics of NCEs under synthesis. Similar examples have been reported elsewhere [11—13]. 

---