Exponential dosing profile

Figure 6.38 shows three dosing profiles for a zero initial concentration of dye in the mixing tank and a dosing time of 40. The solid, dotted and dashed lines represent hnear, exponential and quadratie dosing profiles, respectively. 

Linear (solid line), exponential (dotted line) and quadratic (dashed line) dosing profiles. 

The rates of movement of foreign compound into and out of the central compartment are characterized by rate constants kab and kei (Fig. 3.23). When a compound is administered intravenously, the absorption is effectively instantaneous and is not a factor. The situation after a single, intravenous dose, with distribution into one compartment, is the most simple to analyze kinetically, as only distribution and elimination are involved. With a rapidly distributed compound then, this may be simplified further to a consideration of just elimination. When the plasma (blood) concentration is plotted against time, the profile normally encountered is an exponential decline (Fig. 3.24). This is because the rate of removal is proportional to the concentration remaining it is a first-order process, and so a constant fraction of the compound is excreted at any given time. When the plasma concentration is plotted on a logio scale, the profile will be a straight line for this simple, one compartment model (Fig. 3.25). The equation for this line is... 

The absorption of freely soluble drugs having various values of k a was studied. Initially, the relationship between the simulated k a values and the corresponding conventional ka values, which are computed from the simulation assuming first-order absorption, was explored. An amount of instantly dissolved mass of q0 = 20, 000 was inserted in the input end of the tube and both profiles of the fraction of the mass that was absorbed and exited the tube were recorded. To find out the relationship between k a and ka, the following exponential equation was used to fit the simulated data of the fraction of dose absorbed Fa vs. time ... 

Single-dose and steady-state multiple-dose plasma-level-vs.-time profiles of tolrestat, an aldose reductase inhibitor, were compared. The terminal exponential-phase half-life was 31.6 hours at the conclusion of multiple-dose therapy administered at a 12-hour dosing interval. However, there was little apparent increase in plasma concentrations with repetitive dosing, and the cumulation factor, based... 

When a drug is administered as an i.v. bolus, the entire dose of the drug is injected straight into the blood. Therefore, the absorption process is considered to be completed immediately, and the concentration-time profile of fhe drug in plasma will be determined by the rate of distribution and elimination. When the distribution of the drug is very fast, the plasma concentration-time curve is determined only by the elimination rate and shows a mono-exponential (first-order) decline (a theoretical example is shown in Figure 31.7a ... 

Salmonson et al. [54] also described the pharmacokinetics of rHuEPO after intravenous and subcutaneous administration of 50U/kg to six healthy male volunteers. The calculated mean values for volume of distribution at steady state and clearance after an i.v. dose were 76 33 mL/kg and 12.0 + 3.0mL/h/kg, respectively. Serum concentrations of rHuEPO peaked at 13.0 6.0h after the s.c. dose and the bioavailability over 72 h was 36 23%. The mean residence time and half-life of rHuEPO were 6.2 1.0 and 4.5 0.9 h after i.v. and 46 18 and 25 + 12h after s.c. administration. They found that the serum concentration time profiles after i.v. adminisitaration followed a mono- or bi-exponential decline, and the elimination after s.c. dose was described by a mono-exponential decline. 

They found that a profile which has a retarding field over a portion of the base and an aiding field over the other improves the figure of merit compared with the exponential distribution. Ion implantation could be used to shape this profile. By using ion implantation, the base Gummel number can be precisely controlled since the use of current integration for the dose measurement allows the base impurities to literally be counted. Further discussion of the device parameter optimization by ion implantation is treated by Stone and Plunkett in Reference 26. 

Figure 6. PARP-2" mice are sensitive to ionizing radiation. A) Kaplan-Meier survival curves after 8 Gy of whole body irradiation. Wilcoxon test p(PARP-2 vs PARP-2 ) < 10. (Taken from Minissier-de Murcia et al, with permission). B) Comparison ofy-ray survival curves of wild-type, PARP-T and PARP-2 mouse 3T3 fibroblasts. 10 fibroblasts from mid-log growing subcultures were plated in triplicate in 25 cm flasks and returned to the incubator overnight prior to irradiation. Following treatment, the flasks were supplied with 8 ml fresh medium and grown for exacdy 5 doubling times (relative to mock irradiated cells) with two changes of medium. Cells were harvested by trypsin-EDTA and scored visually under microscope. PARP-1, PARP-T and PARP-2 fibroblasts yielded a convex curve which fitted a linear-quadratic dose-dependent equation, as most usually found among various cell lines, with a pseudo-plateau relating to Cl arrest. PARP-2 fibroblasts showed a concave profile and fitted a double-exponential equation. PARP-2 fibroblasts were clearly the most sensitive ones in the low dose rai of radiation (insert) Bars,SD.

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