Blood levels steady state

Medroxyprog esteroneAcetate. Accurate pharmacokinetic and metaboHsm studies on MPA have been difficult because the radioimmunoassays employed caimot differentiate between MPA and its metaboHtes (346). Comparison of MPA plasma levels assayed by hplc and radioimmunoassay show that radioimmunoassay may overestimate intact MPA concentrations by about fivefold (347). However, values of the mean elimination half-life of MPA were similar, being 33.8 and 39.7 h when measured by hplc and radioimmunoassay, respectively (347). Approximately 94% of MPA in the blood is bound to albumin (348). When taken orally, MPA is rapidly absorbed with Htde or no first-pass metaboHsm (13). Peak semm levels ate reached after 3 h. Steady state occurs after three days of daily adininistration (349). The pharmacokinetics of MPA when adininistered in a depot formulation have been described (350). 

Phenytoin s absorption is slow and variable yet almost complete absorption eventually occurs after po dosing. More than 90% of the dmg is bound to plasma protein. Peak plasma concentrations are achieved in 1.5—3 h. Therapeutic plasma concentrations are 10—20 lg/mL but using fixed po doses, steady-state levels are achieved in 7—10 days. Phenytoin is metabolized in the fiver to inactive metabolites. The plasma half-life is approximately 22 h. Phenytoin is excreted primarily in the urine as inactive metabolites and <5% as unchanged dmg. It is also eliminated in the feces and in breast milk (1,2). Prolonged po use of phenytoin may result in hirsutism, gingival hyperplasia, and hypersensitivity reactions evidenced by skin rashes, blood dyscrasias, etc... 

Absorption kinetics of trichloroethylene are often monitored by measuring levels in the blood during and after exposure. Volunteers who inhaled 100 ppm for 6 hours showed a peak blood trichloroethylene level of approximately 1 pg/L after 2 hours (Muller et al. 1974). These levels fell rapidly when exposure ceased. Trichloroethylene levels in blood and breath increased rapidly in another study after initiation of a 4-hour exposure to 100 ppm, reaching near steady-state within an hour from the start of the exposure (Sato and... 

Measurement of steady-state H2S levels in blood and tissue... 

After an erythropoietic agent is initiated, hemoglobin response is typically delayed. Steady-state hemoglobin levels do not occur until after the life span of a red blood cell (mean 2 months range 1 to 4 months). To avoid... 

As shown in double-blind, placebo-controlled, randomized studies with healthy subjects, both infused [145] and oral [146] L-arg significantly inhibited (by =40%) ADP-induced platelet aggregation in vitro and potentiated platelet cGMP content. The effect, though, was weak the plasma concentration of L-arg required to produce an anti-platelet effect was some 2-fold above normal, steady-state levels, and the oral anti-aggregatory L-arg dose was 4-fold greater than the usual daily L-arg intake in humans. The infused L-arg dose that effectively inhibited platelet activity (30 g total) was hypotensive and increased heart rate, whereas the oral anti-platelet dose (7 g per day over 3 days) did not affect blood pressure, suggestive of oral L-arg platelet selectivity. 

A microdialysis study was carried out to examine transport of oxycodone into the brain of rats [67], Oxycodone was administered by i.v. infusion, and unbound drug concentrations were monitored in both vena jugularis and striatum. Steady-state equilibrium was reached rapidly and drug levels in the two compartments declined in parallel at the end of the infusion. An unbound brain to unbound plasma ratio of 3.0 was measured which is 3- to 10-fold higher than for other opioids, and explains the similar in vivo potency of oxycodone in spite of lower receptor affinity. The authors interpret these data as de facto evidence of the existence of an as-yet unidentified transporter that carries oxycodone across the blood-brain barrier. 

For clinical chemistry the most important question is whether or not changes in enzyme activity will accompany defined disease states, the materials being obtainable by ways practicable in clinical medicine. The enzyme levels of G-6-PDH and 6-PGDH are assayed in serum, blood (hemolyzates), and liver homogenates yielded by biopsy. In the latter case it is necessary most of all to take account of the probable differences between the assay conditions and the steady state. Furthermore, the reference system is of decisive importance (e.g., cellularity... 

Venous blood levels of cyanide reached a steady state (mean value, 200 g/100 mL) within 10 min of exposure of cynomolgus monkeys at 100-156 ppm (Purser et al. 1984). The blood level stayed constant during the remainder of the 30-min exposure, during which time the animals lost consciousness the blood level remained the same for 1 h after exposure, even though the monkeys recovered consciousness within 10 min. The mean concentration of whole blood cyanide in rabbits that died following inhalation exposure was 170 pg/100 mL the mean plasma concentration was 48 figHOO mL (Ballantyne 1983). 

In a study where blood n-hexane concentrations were determined in volunteers during exposure to 102 or 204 ppm for 4 hours, blood -hexane reached steady-state within 100 minutes and was stable until the end of exposure. Concentrations of n-hexane in blood at 100 minutes were 0.202 mg/L at 102 ppm and 0.357 mg/L at 204 ppm. After exposure, there was a rapid fall to about 50% of the level at the end of exposure in the first 10 minutes and a slower exponential time course with a half-life of 1.5-2 hours (Veulemans et al. 1982). 

Clearance of nicotine is decreased in the elderly (age >65) compared to adults (Molander et al. 2001). Total clearance was lower by 23%, and renal clearance lower by 49% in the elderly compared to yonng adults. Lower nicotine metabolism in the elderly may be contribnted to by rednced liver blood flow, since no decrease in CYP2A6 protein levels or nicotine metabolism in liver microsomes due to age has been detected (Messina et al. 1997). No differences in steady-state nicotine plasma levels or estimated plasma clearance valnes were detected in three age gronps (18-39, 40-59, and 60-69 years) nsing patches with the same nicotine content (Gonrlay and Benowitz 1996). The volnme of distribntion of nicotine is lower in older snbjects due to a decrease in lean body mass (Molander et al. 2001). 

The relationship between nicotine intake and steady state cotinine blood levels can be expressed in the following way, based on steady state exposnre conditions Dnic = CLcot X CcoT f, where Dnic is the intake (dose) of nicotine, CLcot is the clearance of cotinine, Ccot is the steady state blood concentration of cotinine and f is the fraction of nicotine converted to cotinine. On rearranging the equation, Dnic = (CLcot f) x Ccot = K x Ccot where K is a constant that converts a given blood level of cotinine to nicotine intake. On average, K = 0.08 mg 24h ng ml (range 0.05-1.1, CV = 21.9%). Thus, a cotinine level of 30 ng ml in blood corresponds on average to a nicotine intake of 24 mg per day. 

Consideration will be given mainly to the principles of pharmacokinetics and methods of measuring drugs whose effectiveness derive from their ability to alter the patient s own metabolism, either locally or generally, and for which there is reasonable evidence that therapeutic responsiveness and/or toxicity is related to the steady-state blood drug level. 

It is hardly surprising that blood phenytoin levels bear little relation to the total daily dose (B4, B5, Cl, G4, G6, L12), or that the concept of the steady-state blood levels frequently docs not hold in clinical practice (B7, M15). This indicates the necessity for regulating phenytoin therapy on the basis of blood concentrations, assuming that this bears a reasonably close correlation to the therapeutic effect. Conclusive evidence of the validity of this basic assumption is lacking (Table 1). 

Plasma steady-state levels of up to 10 /ig/ml are occasionally necessary for control of ventricular arrhythmias but cannot always be tolerated without serious toxic effects. Of thirteen patients referred to a specialist coronary care unit because of reputed refractoriness to the therapeutic effect of lignocaine, in only four was the diagnosis substantiated by demonstrating failure of therapeutic response to blood lignocaine concentrations in excess of 10 /tg/ml (H8). In four patients a therapeutic response was observed at blood lignocaine levels between 5 and 10 /xg/ml, and another five patients were responsive to lignocaine blood levels within the usual therapeutic range. 

---