Maximum drug concentration

FIGURE 3.1 Absorption curve for an orally administered drug. maximum concentration A a, rate of absorption A (.. rate of elimination and A m, rate of metabolism. 

Drug Maximum Concentration [%] Matrix LCNP Structure Reference... 

Figure 4 shows the concentration range determined for each investigated drug and metabolite in the surface and wastewaters collected in the Ebro River basin, and its comparison with the drug levels found in similar studies carried out in other locations of Spain [6, 7,12,13,19, 31-33] and in various countries of the American [5, 10, 15, 22, 23] and the European continents [8, 9, 11, 14, 16-18, 21, 24-30]. Drug residue levels found in influent and effluent wastewaters from the Ebro River basin were mostly between the minimum and maximum concentrations described for these compounds in the peer-reviewed literature. Only, few compounds, e.g.,... 

AUC, area under the curve, Cmax, maximum concentration MAOI, monoamine oxidase inhibitor TCA, tricyclic antidepressant. Recommended first-line drug interaction search engines Lexi-Comp, Inc Lexi-Comp Online, http //online.lexi.com and Thomson MICROMEDEX Healthcare Series https //www.thomsonhc.com. 

Peak plasma levels are reached about 1.5 h after oral ingestion, the maximum concentrations being in the order of 2 - 3 ng equivalents/ml (parent drug + metabolites) for an oral 1 mg dose. The elimination from the plasma is biphasic and proceeds with mean half-lives of 6 h (a-phase) and 50 h ((3-phase). Similar elimination half-lives are obtained from the urinary excretion. The cumulative renal excretion is practically the same after oral and intravenous administration and amounts to 6 - 7 % of the radioactivity dosed. The main portion of the dose, either oral or intravenous, is eliminated by the biliary route into the faeces. The kinetics of bromocriptine has been demonstrated to be linear in the oral dose range from 2.5 to 7.5 mg. 

Dissolution indicates the rate-limiting step for compound absorption when drugs are administered orally. The solubility of a pharmaceutical compound represents its maximum concentration in an aqueous buffer. Additional compound will not dissolve above this concentration. The solubility value is often heavily dependent upon pH and temperature and is typically measured at physiologically important pH levels and body temperature. The standards for dissolution testing are determined by the United States Pharmacopoeia (USP). Testing typically requires sampling of a solution at 15, 30, 45, and 60 min for immediate-release products. /./Pl.C is ideally suited for use in conjunction with USP apparatus types I or II and can rapidly analyze multiple time points or replicate samples. 

Upon absorption, the plasma concentration of the drug continues to rise until it reaches the maximum concentration. Cmax. At Cmax, the rates of elimination processes such as metabolism and excretion, which also begin to operate on the drug as soon as it enters the body, equal the rate at which it is absorbed (Fig. 3.1). Throughout the absorption process, the drug rapidly distributes to the red blood cells, organs, and all intra- and extracellular... 

The Time for Maximum Concentration, 7max, is the third important component of bioavailability studies. It is a measure of the rate of drug absorption. A lower 7max represents a faster absorption and a higher Tmax represents a slower absorption. Similar to Cmax, the 7max is read directly from the plasma concentration versus time profile. The 7max in Figure 12.2 is 6 hours. 

Somewhat surprisingly, microdialysis has also revealed that the time to maximum concentration (T ax) within the CNS is close to the Tj ax value in blood or plasma, irrespective of lipophilicity. For example, the CNS Tj ax for atenolol (log D7 4 = - 1.8) occurs at 2 min in the rat after intravenous administration [8]. In addition the rate of elimination (half-life) of atenolol and other polar agents from the CNS is similar to that in plasma or blood. The implication of these data is that poorly permeable drugs do not take longer to reach equilibrium with CNS tissue than more lipophilic agents... 

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. 

Maximum concentration (Cmax) and exposure (AUQ in toxicity studies at NOAEL using the most sensitive species, based on the concentrations of drug unbound to plasma proteins (for which substantial corrections may be necessary if plasma protein binding in one or more species is above 95%)... 

Probucol, introduced relatively recently as an antihypercholesteremic drug, differs chemically from other drugs. Chemically, probucol is ort/io-di-tertbutyl substituted b -mercap-tophenol. The mechanism of action of probucol is unknown. Being a lipophilic compound, it is easily distributed into fatty tissue and, as a result, approximately 20% of its maximum concentration in the blood is still maintained for 6 months. 

Drug/Food interactions The time to maximum concentration of zonisamide is delayed in the presence of food, but no effect on bioavailability occurs. 

Drugs that may interact with pilocarpine include beta blockers and anticholinergics. Drug/Food interactions The rate of absorption of pilocarpine is decreased when taken with a high-fat meal. Maximum concentration is decreased and time to reach maximum concentration is increased. 

It has to be emphasized that drug only appears to be distributed in this volume we have not measured any volume directly, but simply divided dose by maximum concentration, i.e. Vd is, mathematically, a proportionality constant. 

Again we will take blood samples at intervals after dosing, measure plasma drug concentrations, and plot the results on a linear graph (Fig. 11). The first and obvious thing to note is that the plasma concentrations rise to a maximum at around 1 h, whereas, of course, the early plasma concentrations taken soon after the intravenous bolus were the highest. The time to reach the peak plasma concentration after an oral dose is often abbreviated to Tmax, and the concentration itself to Cmax - the maximum concentration achieved after that dose. 

Concentration-time profile for a hypothetical drug administered intravenously. Following intravenous dosing of a drug, blood concentrations of the drug reach a maximum almost immediately. Y-axis is logarithmic scale. 

Concentration-time profile for a hypothetical drug administered extravascularly. C ,ax, maximum concentration achieved. T ax. time required to achieve maximum concentration. AUC = Area under the curve. Y-axis is on logarithmic scale. 

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-... 

FIGURE 4.2 A Effect of differences in elimination rate ion the maximum concentration (C, J and time to maximum concentration (F ax) reached after a single oral dose. The drug absorption rate is the same (Ka = 1 h ) for curves A and B. The for curve A is 6 hours the P for curve B is 2 hours. B Differences between absorption rates can have a pronounced effect on the time (T ax) which the maximum concentration (C ,x) reached. Curve A shows an orally administered drug with an absorption rate 4 times faster than that of curve B. Curve C shows the effect of a 50% decrease in bioavailability of drug A. The half-life (4 hours) is similar for scenarios A-C. 

Sterility test validations are performed per current USP Section <71>. The validation is performed on a single lot of the largest volume, highest product strength to simulate the maximum concentration of active drug substance on the membrane hlter. 

Febuxostat is more than 80% absorbed following oral administration. Maximum concentration is reached in approximately 1 hour. Febuxostat is extensively metabolized in the liver. All of the drug and its metabolites appear in the urine although less than 5% appears as unchanged drug. Because it is highly metabolized to inactive metabolites, no dosage adjustment is necessary for patients with renal impairment. 

Pharmacokinetic studies in pigs following a single oral administration of 20 mg kitasamycin/kg bw showed that the drug was rapidly absorbed and distributed in the body. A maximum plasma concentration of 4.5 ppm was attained within 0.5 h, the half-life in plasma being 0.7 h. Highest tissue residue concentrations (21 ppm) were detected in kidney within 1-2 h. The ratio of the maximum concentrations determined in kidney to that in liver was around 3 2. 

The disadvantages of CD include (i) strict correlation between the structure of the guest molecule and the cavity size of the CD molecule (ii) limited solubility of CD in water, and thus limited the maximum concentrations this approach can achieve and (iii) CDs can signiLcantly modify absorption-distribution-metabolism-excretion/elimination (ADME) parameters if the binding constant K is too high, and thus limited the amount of free drug for absorption (Miller et al., 2006). 

---