Plasma Subject

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. 

Rhabdomyolysis is a problem with several lipid-lowering drugs (SEDA-13, 1325 SEDA-13, 1328 SEDA-13, 1330 SEDA-19, 409), especially when they are used in combination (37). In individuals with pre-existing renal insufficiency this can lead to an earlier need for chronic dialysis (38). All statins can cause myopathy and rhabdomyolysis, but not all statins are alike. For example, the evidence to date, based on almost 2 decades of experience, points to an extremely low risk of myopathy and rhabdomyolysis with lovastatin, and lovastatin 20 mg tablets are being considered for non-prescription availability in several countries (39). Furthermore, muscle adverse effects do not necessarily occur after a change from one statin to another (40). Interactions between various hypolipidemic drugs and other drugs also sometimes cause rhabdomyolysis (SEDA-18, 426). For instance, itraconazole markedly increases plasma concentrations of lovastatin, and in one subject plasma creatine kinase was increased 10-fold within 24 hours of administration of this combination (41). 

A standard double-sandwich enzyme-linked immunosorbent assay (ELISA) or Western blot analysis is used. As the concentration of factor is very low in normal plasma (approximately 0.1 mg/1 for factor VIII), it is necessary to subject plasma samples to cryoprecipitation in order to concentrate the sample, prior to Western blot analysis. The cryoprecipitation protocol described by Bi et al. is as follows (Bi et al., 1996 Sarkar et al., 2000 Mah et al., 2003). Plasma samples are collected as described above for the Coatest assay. Plasma is then frozen at -80 °C overnight. Frozen samples are then subject to centrifugation at 7000 x g for 20 min at 4°C. The precipitate is washed with... 

The influence of three dietary factors - pectin, cellulose and phytates - on plasma uptake of manganese (Mn) was studied in adults administered Mn tolerance tests. Plasma samples were collected at hourly intervals following administration of various doses of several Mn salts. It was found that a 40 to 50 mg dose of elemental Mn was necessary to produce consistent plasma responses and that manganese chloride (MnCl ) was better absorbed than the sulfate or acetate form. In fasting subjects, plasma Mn was 0.64, 1.29, 1.12, 0.95, and 0.75 ug/L at hours 0, 1,... 

After a rapid intravenous injection of 0.5 mg/kg to 6 subjects, plasma concentrations of about 0.8 pg/ml were measured after 5 minutes, declining to 0.07 ig/ml at 5 hours (D. L. Fung et al., ibid.). 

Following an intravenous dose of 1 mg to 6 subjects, plasma concentrations of about 0.25 ig/ml were observed at 2 minutes decreasing to 0.005 pg/ml at 20 minutes following an intramuscular dose of 1 mg to 4 subjects, peak plasma concentrations of about 0.003 pg/ml were attained in 30 minutes (L. Berghem t a/., Br. J. Anaesth., 1980,52, 597-601). 

After a single oral dose of 600 mg, administered to 6 subjects, plasma concentrations of 34 to 54pg/ml (mean 43) were attained in 4 hours (A. E. S. Ritch et ai, Br. J. din. Pharmac., 1982,14,116-119). Steady-state plasma concentrations of 32 to 89 pg/ml (mean 57) were reported during the daily administration of 800 mg to 10 subjects (S. Thune, Curr. med. Res. Opinion, 1976, 4, 70-75). 

Following a single oral dose of 5 mg to 7 subjects, peak plasma concentrations (bezitramide plus major metabolite) of about 0.005 pg/ml were attained in about 3 hours in 3 of the subjects, plasma concentrations remained fairly constant over a period of 7 hours in a further 2 subjects, distinct secondary peak plasma concentrations were observed (D. K. F. et al., Eur. J. din. Pharmac., 1984,27, 615-618). 

A single oral dose of 200 mg given to 5 subjects, produced peak plasma concentrations of 2.9 to 4.1 pg/ml (mean 3.6) in 0.6 to 2 hours following oral doses of 200 mg daily for 3 days to 2 subjects, plasma concentrations of 6.5 and 6.4 pg/ml were observed 9 hours after the last dose (D. D. Breimer, Eur. J. clin. Pharmac., 1976,10, 263-271). 

After a single oral dose of400 mg to 4 subjects, peak plasma concentrations of 4.9 to 9.9 jig/ml (mean 7) were attained in 1 to 2 hours following oral doses of 150 mg three times a day for 3 days to 4 subjects, plasma concentrations of 5.8 to 8.4 pg/ml (mean 6.8) were reported 2 hours after the final dose (E. W. McChesney ta/., Biochem. Pharmac., 1967,16, 813-826). 

On the first day after termination of therapy with oral doses of 50 mg thrice daily to 4 subjects, plasma concentrations of norcyclizine were in the range of 0.004 to 0.022 pg/ml (mean 0.014) (R. Kuntzman et ai, J. Pharmac. exp. Ther., 1967,158, 332-339). 

Daily oral doses of 75 to 200 mg given to 5 subjects, produced steady-state plasma concentrations of 0.05 to 0.15 pg/ml of doxepin in two of these subjects plasma concentrations for monodesmethyldoxepin of 0.09 and O.lOpg/ml were reported (J. E. O Brien and O. N. Hinsvark, J. pharm. Sci., 1976,65, 1068-1069). 

Following oral administration of 200 mg three times daily for 4 days to 10 subjects, plasma concentrations of 0.3 to 17 pg/ml (mean 6.4) were reported 2 hours after the morning dose (R. A. Buchanan et al. Cun. ther. Res., 1969,11, 533-538). 

After a single oral dose of 60 mg given to 5 subjects, peak plasma concentrations of 0.05 to 0.09 pg/ml (mean 0.07) were attained in 2 to 4 hours. Following oral administration of 30 mg three times daily to 4 subjects, plasma concentrations of 0.03 to 0.08 pg/ml (mean 0.06) were reported 10 hours after the final daily dose on day 21 (G. Caille et al., ibid.). 

After a single oral dose of 2 mg/kg given to 6 subjects, peak plasma-lofepramine concentrations of 0.04 to 0.14pg/ml (mean 0.09) were attained in about 1 hour peak plasma-desipramine concentrations of 0.01 to 0.02 pg/ml were attained in 3 to 8 hours in 4 subjects. When a similar dose was given to the same subjects on a second occasion some weeks later, peak plasma-lofepramine concentrations of 0.05 to 0.27 pg/ ml (mean 0.13) were reported. Following oral doses of 70 mg three times a day for 10 days to 3 subjects, plasma concentrations of about 0.003 pg/ ml of lofepramine and 0.01 to 0.05 pg/ml (mean 0.025) of desipramine were reported, determined immediately prior to a dose (G. P. Forshell et al., Eur. J. clin. Pharmac., 1976, 9, 291-298). 

A single oral dose of 160[ig was administered to 13 subjects plasma concentrations measured at intervals over a period of hours varied considerably but were in the range 0 to 0.009 pg/ml (D. G. Upshall and D. G. Wailling, Clinica chim. Acta, 1972, 36, 67-73). 

Following a single oral dose of 50 mg to 8 subjects, peak plasma concentrations of 0.08 to 0.18 pg/ml (mean 0.13) were attained in about 3 hours plasma concentrations were higher in 4 subjects who were poor metabolisers of debrisoquine in comparison with the 4 extensive metabolisers(N. S. Oates era/., Clin. Pharmac. Ther., 1983,34, 827-834). Following daily oral doses of 50 mg three times a day to 8 subjects, plasma concentrations of 0.10 to 0.24 ig/ml (mean 0.18) were reported 2 hours after a dose (J. Karam et al. Diabetes, 1974, 23, Suppl. 1, 375). 

After a single oral dose of 30 mg to 10 subjects, peak plasma concentrations of 0.19 to 0.40 pg/ml (mean 0.3) of desmethyldiazepam were reported in 2 to 8 hours a second peak plasma concentration was reported for each subject. Following oral administration of 20 mg three times a day for 3 days to 5 subjects, plasma concentrations averaged 0.8 pg/ml 12 hours after the final dose (R. R. Brodie et al., Biopharm. Drug Disp., 1981,2, 59-68). 

After a single oral dose of400 mg given to 5 subjects, plasma concentrations of 7 to 13pg/ml (mean 10) were attained in 1 hour. Oral dosing of 5 subjects with 400 mg three times a day for 5 days, produced peak plasma concentrations of 12 to 25 pg/ml (mean 18) on the 5th day (C. Graffner et al., Acta pharm. suec., 1973,10, 425-434). 

Following chronic oral administration of 15 to 60 mg daily in divided doses to 15 subjects, plasma concentrations, determined 2 to 21 hours after the last daily dose, were in the range 0.010 to 0.023 pg/ml (mean... 

SEDA-19, 409), especially when they are used in combination (26). In individuals with pre-existing renal insufficiency this can lead to an earlier need for chronic dialysis (27). Interactions between various hypolipidemic drugs and other drugs also sometimes cause rhabdomyo-lysis (SEDA-18,426). For instance, itraconazole markedly increases plasma concentrations of lovastatin, and in one subject plasma creatine kinase was increased 10-fold within 24 hours of administration of this combination (28). 

Interpretation In normal subjects, plasma ACTH concentrations peak 30 minutes after CRH injection (80 7pg/mL at 0930 hr 29 2.6pg/mL at 2030 hr), and serum cortisol peaks at 60 minutes (13 Ijig/dL at 1000 17 0.7p.g/dL at 2100 hr). Patients with pituitary ACTH deficiency (secondary adrenal insufficiency) have decreased ACTH and cortisol responses. Patients with hypothalamic disease have prolonged ACTH responses and subnormal cortisol responses. Most patients with Cushing s syndrome caused by adrenal tumors or nonendocrine ACTH-producing tumors do not respond to CRH. Most patients with Cushing s syndrome respond with a normal or excessive increase in ACTH. Responses are usually normal in patients with depression. 

Some examples of chiral HPLC separations of racemic drugs are the following. Typical chromatograms of the simultaneous determination of isopyramide and its active metabolite, mono-N-dealkyldisopyramide, in drug-free human plasma, human plasma spiked with dis-opyramide and mono-N-dealkyldisopyramide, and treated subject plasma are presented in Fig. 

THCCOOH concentrations were monitored in human plasma for 7 days after controUed cannabis smoking (Huestis et al. 1992b). This inactive metabolite was detected in all subjects plasma by 8 min after the start of smoking. THCCOOH concentrations in plasma increased slowly and plateaued for up to 4 h. Peak concentrations were consistenUy lower than peak THC concentrations, but... 

After oral and sublingual administration of THC, THC-containing food products, or cannabis-based extracts, concentrations of THC and 11-OH-THC are much lower than after smoked administration. Plasma concentrations of THC in patients receiving 10 to 15 mg of Marinol as an anti-emetic were low to non-measurable in 57 patients (Shaw et al. 1991). Brenneisen et al. found peak plasma concentrations of THC and THCCOOH after daily oral 10 to 15 mg Marinol doses of 2.1 to 16.9 ng/ml within 1 to 8 h and 74.5 to 244 ng/ml within 2 to 8 h, respectively (Brenneisen et al. 1996). In our oral THC controlled administration studies, peak plasma THC, 11-OH-THC, and THCCOOH concentrations were less than 6.5,5.6, and 24.4 ng/ml, respectively, following up to 14.8 mg/day of THC in the form of THC-containing food products or Marinol (Nebro et al. 2004). Peak concentrations and time to peak concentrations varied, sometimes considerably, between subjects. Plasma... 

Neat VX, 20 ig kg-1, was applied to the skin of four subjects, while four other subjects received 20 p.g kg-1 mixed 1 1 with octylamine, and four others received neat VX, 35 pg kg-1 (Lubash and Clark, 1960). Seven were symptomatic with insomnia, nightmares, lightheadedness, nausea, epigastric discomfort, vomiting and diarrhea. (The whole blood activity was 14-38% of control in these subjects.) The whole blood erythrocyte activity was above 42% of control activity in the five asymptomatic subjects. Plasma and urinary electrolytes, BSP excretion, SGOT, SGPT and serum amylase were all normal following exposure. 

To assess whether food impacted the pharmacokinetics of a new drug, such a study was conducted in 12 healthy, male subjects. Plasma samples were collected and analyzed for drug concentrations. AUC(0—oo) was calculated using the linear trapezoidal rule and Cn3. was determined from direct observation of the data. 

In each of the normal drinkers and in all but one of the heavy drinkers a normal basal B, concentration was found. As a group there was no significant change in plasma B, after alcohol ingestion in the controls but in the heavy drinkers there was a significant increase in plasma B[ that was maximal after 60 min (Fig. 20). However, in two of the control subjects plasma B, also rose to an abnormal level after 60 min and, conversely, two of the heavy drinkers showed no significant rise in B, postalcohol. 

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