Subject plasma levels

Wood, A. ., Bolli, P. and Simpson, K O., (1976) Prazosin in normal subjects plasma levels, blood pressure and heart rate. Brit. J. clin. Pharmacol, 3, 199. 

AUC.dat Sixty-nine subjects were exposed to three different medications containing the same drug substance in a test of equivalence each had blood samples withdrawn at defined time points after administration so as to obtain a curve of plasma level of drug vs. time. The area under such a curve is a measure for the amount of medication the subject s body absorbed through... 

Fig. 15 Mean plasma levels for groups of ten human subjects receiving single 0.5-g doses (as two 250-mg capsules) of chloramphenicol preparations A, B, C, or D. Vertical lines represent one standard error on either side of the mean. (From Ref. 19.).

Portmann and co-workers then studied the kinetic pathways in man for hydroxynalidixic acid, the active primary metabolite.(26) The rate constants for glucuronide formation, oxidation to the dicarboxylic acid and excretion of hydroxynalidixic acid were calculated. Essentially total absorption of hydroxynalidixic acid was found in every case. Good agreement between experimental and theoretical plasma levels, based on the first order rate approximations used for the model, was found. Again, the disappearance rate constant, kdoi was found to be very similar for each subject, although the individual excretion and metabolic rate constants varied widely. The disappearance rate constant, k was defined as the sum of the excretion rate constant, kg j and the metabolic rate constants to the glucuronide and dicarboxylic acid, kM-j and kgj, respectively. 

The plasma levels of triprolidine hydrochloride were determined in 16 normal male subjects.12 When administered orally at a concentration of 3.75 mg triprolidine hydrochloride in 15 ml of syrup, peak plasma levels of 8.2 ng/ml were achieved in 2 hours with a drug half-life of 5 hours. The low plasma levels found indicate a large volume of tissue distribution which was consistent with data obtained from rat studies. 

When individuals were administered 800 mg. per day of phenylbutazone (Butazolidin) for 14 days or more, each developed a characteristic plasma level.39 For 60 subjects this level ranged from 60 to 150 mg. per liter and was constant from day to day for individuals. It was concluded that the rate at which the drug was metabolized under the conditions used varied from 17 to 35 per cent per day for different individuals. It is interesting that the "biological half-life" of this substance varies from species to species3 hours for rabbits, 6 hours for dogs and rats, 72 hours for man. It is also clear from the above that its rate of disappearance varies widely for individual human subjects. 

Six patients with Parkinson s disease were withdrawn from their antiparkinsonian medications (L-DOPA/carbidopa, bromocriptine, or lisuride) (Rabey et al. 1992, 1993). After 12 hours off medication, the subjects ate 250 g of cooked fava beans. Significant improvements in motor symptoms were noted, comparable to those seen with 125 mg of L-DOPA and 12.5 mg of carbidopa. In fact, three subjects developed severe dyskinesias after fava ingestion, akin to those seen after larger doses of pharmaceutical L-DOPA. Plasma levels of L-DOPA increased after fava ingestion in a manner comparable to that seen with administration of oral L-DOPA. These results suggest that the L-DOPA contained in fava beans was transported into the CNS and converted to dopamine. In five nonparkinsonian, healthy volunteers, a similar increase in plasma L-DOPA was observed after fava ingestion, although much lower. The difference in plasma L-DOPA between normal volunteers and parkinsonian patients is apparently due to a residual effect of carbidopa in the subjects with Parkinson s disease. Without carbidopa, the L-DOPA from fava is rapidly converted to dopamine in the blood stream and never crosses the blood-brain barrier. 

A review of case reports, clinical trials, post-marketing surveillance, and drug monitoring studies concurrently showed that the most common side effects were gastrointestinal, dizziness/confusion, and sedation (Ernst et al. 1998). Importantly, the side effects of hypericum in this study were comparable to placebo levels. A pharmacokinetic study showed that plasma levels of up to 300 ng/ml were well tolerated. Headache occured in one subject who was taking 1200 mg extract (59 mg hyperforin, plasma cone. >400 ng/ml) (Biber et al. 1998). 

Tokuda, T., Tamaoka, A., Matsuno, S., et al. (2001) Plasma levels of amyloid-beta proteins do not differ between subjects taking statins and those not taking statins. Arm. Neurol., 49, 546-547. 

The plasma level of fatty acids in a fed subject is between 0.3 and 0.5 mmol/L. As discussed above, the maximal safe level is about 2 mmol/L. This is not usually exceeded in any physiological condition since, above this concentration, that of the free (not complexed with albumin) fatty acids in the blood increases markedly. This can then lead to the formation of fatty acid micelles which can damage cell membranes the damage can cause aggregation of platelets and interfere with electrical conduction in heart muscle (Chapter 22). The cells particularly at risk are the endothelial cells of arteries and arterioles, since they are directly exposed to the micelles, possibly for long periods of time. Two important roles of endothelial cells are control of the diameter of arterioles of the vascular system and control of blood clotting (Chapter 22). Damage to endothelial cells could be sufficiently severe to interfere with these functions i.e. the arterioles could constrict, and the risk of thrombosis increases. Both of these could contribute to the development of a heart attack (Chapter 22) (Box 7.4). 

Phase I data were presented at the 95th AACR meeting, March 2004. Normal healthy male volunteers were subjected to bone marrow aspirations prior to and 4 h following a single 25 mg oral dose of the compound or placebo. L21649 achieved plasma concentrations of 103.4 nM at 4 h post-dose. In July 2004, similar clinical data were presented at the 29th National Medicinal Chemistry symposium. The PK/PD correlated well, and at that time, it was believed that the plasma levels should be closer to the EC90 levels for maximal efficacy. 

M12. Migeon, C. J., Tyler, F. H., Mahoney, J. P., Florentin, A. A., Castle, H., Bliss, E. L., and Samuels, L. T. The diurnal variation of plasma levels and urinary excretion on 17-hydroxycorticosteroids in normal subjects, night workers and blind subjects. J. Clin. Endocrinol. Metab. 16, 622-633 (1956). 

Digoxin is rapidly absorbed from the gut in the fasting subject and reaches a peak concentration in plasma after 30-60 minutes. When taken with food absorption of digoxin is delayed and peak plasma levels occim around 120 minutes after ingestion (W8). Steady-state levels are reached 4-6 hours after the last oral dose. In patients receiving long-term therapy plasma digoxin levels fall slowly with a plasma half-life of about 34 hours (D8). 

Jl, J4, T6). Little benefit can be demonstrated at lower plasma levels. In one study adjustment of dosage to maintain steady-state plasma theophylline levels within a recommended optimum therapeutic range of 10-20 /ig/ml led to improved therapeutic control (J4). To achieve this a more than 8-fold difference in the daily dose was necessary (J4), due to variations between one subject and another in the rate of metabolic degradation of theophylline. 

Absorption - Although well absorbed orally, naltrexone is subject to significant first-pass metabolism with oral bioavailability estimates ranging from 5% to 40%. Following oral administration, naltrexone undergoes rapid and nearly complete absorption with approximately 96% of the dose absorbed from the Gl tract. Peak plasma levels of naltrexone and 6- -naltrexol occur within 1 hour of dosing. 

Absorption/Distribution - Oral absorption is nearly complete. Peak plasma levels are attained at approximately 3 hours. The plasma half-life ranges from 12 to 27 hours after multiple oral doses. Steady-state levels are approached in 3 to 5 days once at steady-state, no accumulation occurs during chronic therapy. Plasma levels are approximately proportional to dose. In patients with congestive heart failure (CHF NYHA class III), the rate of flecainide elimination from plasma is moderately slower than for healthy subjects. Plasma protein binding is about 40% and is independent of plasma drug level over the range of 0.015 to about 3.4 mcg/mL. 

Elderly Plasma levels of carvedilol average about 50% higher in the elderly compared with young subjects. With the exception of dizziness (8.8% in the elderly vs 6% in younger patients), there were no events for which the incidence in the elderly exceeded that in the younger population by more than 2%. 

Fast/Slow acetylators The metabolism of SP to AcSP is mediated by polymorphic enzymes such that 2 distinct populations of slow and fast metabolizers exist. Approximately 60% of the white population can be classified as belonging to the slow acetylator phenotype. These subjects will display a prolonged plasma half-life for SP (14.8 vs 10.4 hours) and an accumulation of higher plasma levels of SP than fast acetylators. Subjects who were slow acetylators of SP showed a higher incidence of adverse reactions. 

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