Blood level curve

Fig. 18 Blood-level curves of identical doses of a drug by parenteral route (I) and by oral route as a solution (II) and as a tablet (III).

Clinically, penamecillin has exhibited the expected activity against infections normally responding to benzylpenicillin [20-22], with the advantage that doses can be given at 8-hourly (instead of 4—6 hourly) intervals and still provide relatively smooth blood-level curves. Organisms producing penicillinases, or those normally tolerant to penicillin G, do not, of course, respond to penamecillin. 

The evaluation of FR 10612 (m-methanesulfonylamino cephalexin) indicated that it was comparable to cephalexin iia vitro, but more effective orally against experimental mouse infections, presumably due to entero-hepatic recirculation also leading to higher and longer blood levels.78 Although apparently dose related, human blood level curves for FR 10612 did show a longer half-life than did cephalexin. Oral cephalosporin candidate SCE-100 (tetrahydro cephalexin) has been examined extensively for in vitro and iin vivo properties.79 It is not as active as cephalexin. 

The differences in blood level curves obtained after the administration of free or complexed drug can be attributed to the different free drug concentrations in the gastrointestinal fluid controlled by the dissolution rate, the solubility and complex dissociation equilibrium. 

Fig.7. Theoretical blood level curves obtained after oral administration of free drug or its cyclodextrin complexes with different stability constants.

Theoretical blood level curves after administering free drug or its cyclodextrin complex with solid cyclodextrin in excess ( stability constant of the complex is 1000 litre mole ad ). 

Table III. Effect of cyclodextrin excess on the peak of the computer simulated blood level curves. ( 2 ) ...

A study in mice showed that orally dosed cefaclor was rapidly absorbed with an efficiency that approached 100% based on a comparison of urinary excretion after oral and parenteral dosage. Blood level curves following oral and parenteral administration supported this conclusion. In addition, cefaclor disappeared from the gastrointestinal tract and appeared in the urine at rates similar to those of cephalexin, a cephalosporin known to be well absorbed orally (W. E. Wright, private communication). 

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). 

Dose-Response Curve for Erythrocyte Protoporphyrin (EP) as a Function of Blood Level in Subpopulations... 

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... 

R3. Roberts, J. G., Neck, I. T., Kallos, J., and Kahn, D. S., D(-)-)-Xylose blood level time-curve as an index of intestinal absorption, with a description of a simplified method for estimation of blood xylose levels. Can. Med. Assoc. ]. 83, 112 (1960). 

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. 

Compartments between which drugs do not mix, or mix only slowly, commonly exist in the body. Metabolism within them is carried out and controlled by enzymes in the usual way. These compartments can be detected by time-curve analysis of the blood levels of drugs. Compartments determined in this way have the limitations that ... 

However, in addition to the dose levels at which the various effects are observed as well as to the steepness of the dose-response curve, the type of the various effects observed is also a very important aspect in the dose-response assessment. If effect A is an alteration in an unspecihc liver enzyme blood level, effect B is an increase in the relative liver weight, and effect C is the incidence of liver tumors, then both effects B and C obviously are evaluated as being more severe effects than effect A i.e., an example of an exception from situation 1 and 3 above. Similarly, effect C is evaluated as being more severe than effect B i.e., an example of an exception from situation 2 above. 

The kinetics of absorption of the drug following administration of the formulation of thiotepa in gelatin particles to rabbits suggested that not only was the blood level elevated compared to a control but the area under the curve (AUC) was essentially more than doubled. Since this represents the amount of drug absorbed the authors suggested that administration of a simple gelatin particulate formulation... 

Reduction in side effects We can use formulation to reduce the rate of dissolution of a drug and thereby reduce the peaks in the blood level versus time curve such that the incidence of side effects can be reduced. 

Poole et al. (1968) administered ampicillin anhydrate and trihydrate to human subjects as 250 mg doses of the suspension or in capsules. The anhydrate gave higher bioavailabilities as measured by th area under the blood level versus time curves. In suspensions, the area ratio (anhydrate/trihydrate was 1.21 and in capsules, this ratio was quite comparable at 1.17. The peak in this curve also occurred earlier for the anhydrate. This was expected based on the 20% higher solubility in water at 3 C (10 mg/ml for the anhydrate and 8 mg/mL for the trihydrate). The difference in dogs was more pronounced suspensions of the anhydrate gave 1.6 times the AUC of suspensions of th< trihydrate form. 

Figure 10.3 Typical curve of the blood levels of a drug after a single oral application. (Source Adapted from PK Tutorial, available from www.pksummits.com)...

FIGURE 18.6 Graded concentration-effect curve for intravenous lidocaine in patients with neuropathic pain. Pain was scored from 0 to 10 with an analog pain scale. The median pretreatment pain score was 7 and a score of 0 meant no pain. Blood levels of lidocaine were measured every 10 minutes and pain was scored at the same time points. The graph relates the blood level of lidocaine to the severity of pain. (Adapted from data published by Ferrante FM, Paggioli J, Cherukuri S, Arthur GR. Anesth Analg 1996 82 91-7.)... 

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