Plasma and cerebrospinal fluid concentrations

Typical Plasma and Cerebrospinal Fluid Concentrations for Some Selected Solutes... 

Bannwarth, B. Netter, P. Lapicque, F. Gillet, R Rere, P. Boccard, E. Royer, R.J. Gaucher, A. Plasma and cerebrospinal fluid concentrations of paracetamol after a single intravenous dose of propaceta-mol. Br.J.Clin.PharmacoL, 1992, 34, 79-81 [plasma CSF LOD 2 ng/mL]... 

C. Mignat, R. Jansen, and A. Ziegler, /. Pharm. Pharmacol., 47, 171 (1995). Plasma and Cerebrospinal Fluid Concentrations of Morphine and Morphine Glucuronides in Rabbits Receiving Single and Repeated Doses of Morphine. 

High plasma concentrations of ascorbic acid are reportedly associated with better memory performance, and lower plasma and cerebrospinal-fluid concentrations of ascorbic acid were found in patients with Alzheimer s disease than in non-demented controls. Individuals who took vitamin C supplements were reported to have a lower prevalence of Alzheimer s disease on follow-up after 4.3 years. However, not all studies have shown a significant association between vitamin C intake or plasma levels and cognitive decline or dementia. 

Wode-Helgodt B, Borg S, Fyro B, et al. Clinical effects and drug concentrations in plasma and cerebrospinal fluid in psychotic patients treated with fixed doses of chlorpromazine. Acta Psychiatr Scand 1978 58 149-173. 

Khaliq Y, Gallicano K, Venance S, et al. Effect of ketoconazole on ritonavir and saquinavir concentrations in plasma and cerebrospinal fluid from patients infected with human immunodeficiency virus. Cbn Pharmacol Ther 2000 68 637-646. 

Nimodipine could be determined by GC in plasma and cerebrospinal fluid at concentrations as low as 1 ng/mL [19]. To avoid decomposition... 

In 1 case of fatal overdosage, a 22-month-old child died 55 hours after ingesting about 5 g of dapsone. The concentrations in the plasma and cerebrospinal fluid were 150 pg/ml and 33 pg/ml, respectively, 42 hours after ingestion. Postmortem concentrations were blood 135 ig/ml, brain 90 ig/g, liver 165 pg/g, and urine 400pg/ml (R. Davies, Lancet, 1950, 1, 905-906). 

Branched-chain-oxoacid dehydrogenase complex, which is responsible for the oxidative decarboxylation of the oxoacids derived from leucine, isoleucine and valine. Increased concentrations of all 3 branched chain amino acids and their oxoacids in urine, plasma and cerebrospinal fluid. Serum tilso contains alloiso-leucine (probably derived from isoleucine). Urine has characteristic odor. Marked cerebral degeneration apparently shortly after birth. Usually fatal within weeks or months of birth. 

Significant correlation was found between plasma and cerebrospinal fluid ascorbic acid levels in demented patients (BarabAs et al. 1995). As a consequence, intravenous infusion of ascorbic acid (2 g), a slow, but marked increase of the concentration in the cerebrospinal fluid was measured by high performance liquid chromatography with electrochemical detection. Ascorbic add level might be an important factor representing the protection of the central nervous system against free radicals. 

Voriconazole is not recommended for use in combination with efavirenz however, if they are co-administered, the dosage of voriconazole should be increased to 400 mg 12-hourly and the dosage of efavirenz reduced to 300 mg/day, in order to provide systemic exposure similar to standard-dose monotherapy [SEDA-32, 498]. The combination of voriconazole and efavirenz in doses adjusted according to steady-state plasma concentrations has been studied in a 40-year-old man with AIDS, cryptococcosis, and mild liver cirrhosis [154 ]. Adequate concentrations of voriconazole in both plasma and cerebrospinal fluid were obtained and target plasma concentrations of efavirenz were achieved at the final dosage adjustment (oral voriconazole 200 mg bd plus oral efavirenz 300 mg/day). There was stable suppression of cryptococcosis and plasma HIV viremia at long-term follow-up (66 weeks), with no significant adverse events. 

Table V contains data for two model substances, p-aminohippurate (PAH) and phenol red. Consideration of the highest values in this table tells you where the major portions of the substances appear. For example, urine and bile show the largest concentrations of PAH and phenol red. Both compounds appear in significant concentrations in the kidney while the values in muscle, brain and cerebrospinal fluid (CSF) are invariably lower than the values seen in plasma. The values in parentheses (Table V) are percent of the administered dose in a given tissue or fluid compartment. They add to the previous information by revealing the overall importance of a particular compartment in the disposition of a substance. For example, while the hepatic concentrations of PAH and phenol red at 4 hrs. are only about 2-fold those of plasma, the large size of the shark liver relative to its body weight, typically about 10%, leads to the appearance of 30-40% of these substances in the liver. The relative handling of these compounds by the urinary and biliary system is obvious from considering the percentage figures. Thus in 24 hours phenol red is about equally distributed in the bile and urine (38 vs 31%) the urinary route is the dominant route of excretion of PAH, i.e., 56 vs 2%.

The use of HPLC to analyze biogenic amines and their acid metabolites is well documented. HPLC assays for classical biogenic amines such as norepinephrine (NE), epinephrine (E), dopamine (DA), and 5-hydroxytryptamine (5-HT, serotonin) and their acid metabolites are based on several physicochemical properties that include a catechol moiety (aryl 1,2-dihydroxy), basicity, easily oxidized nature, and/or native fluorescence characteristics (Anderson, 1985). Based on these characteristics, various types of detector systems can be employed to assay low concentrations of these analytes in various matrices such as plasma, urine, cerebrospinal fluid (CSE), tissue, and dialysate. 

It is not usually possible to measure the concentration of a drug at its sites of action. Plasma, which can be conveniently sampled, is generally used instead, but drug concentrations may be determined in other bodily fluids, such as saliva and cerebrospinal fluid, as well as, of course, the excreta, urine and faeces. There is often a relationship between plasma concentration and response, although this may sometimes... 

Absorption/Distribution - Pyrazinamide is well absorbed from the Gl tract and attains peak plasma concentrations within 2 hours. It is widely distributed in body tissues and fluids including the liver, lungs, and cerebrospinal fluid. Pyrizinamide is approximately 10% bound to plasma proteins. Metabolism/Excretion - The half-life is 9 to 10 hours it may be prolonged in patients with impaired renal or hepatic function. 

Distribution - The steady-state volume of distribution after IV administration was 0.74 L/kg. Cerebrospinal fluid concentrations obtained 0.25 and 5.67 hours post-dose in 3 patients who received 2.5 mg/kg ganciclovir IV every 8 or 12 hours ranged from 0.31 to 0.68 mcg/mL, representing 24% to 70% of the respective plasma concentrations. Binding to plasma proteins was 1 % to 2% over ganciclovir concentrations of 0.5 and 51 mcg/mL. 

Isoniazid does not bind to serum proteins it diffuses readily into all body fluids and cells, including the caseous tuberculous lesions. The drug is detectable in significant quantities in pleural and ascitic fluids, as well as in saliva and skin. The concentrations in the central nervous system (CNS) and cerebrospinal fluid are generally about 20% of plasma levels but may reach close to 100% in the presence of meningeal inflammation. 

Pharmacokinetics and cerebrospinal fluid penetration of hypericin were studied after i.v. dose of 2 mg/kg in monkeys (Table 2) (70). Mean peak plasma concentration of hypericin following this dose was 71.7pg/mL (142 pM). Elimination of hypericin from plasma was biexponential, with an average terminal half-life of 26 14 hours. The 2 mg/kg dose in nonhuman primates was sufficient to maintain plasma concentrations above 5.1 pg/mL (10 pM) for up to 12 hours (the in vitro concentration required for growth inhibition of human glioma cell lines is greater than 10 pM). 

Isoniazid is readily absorbed from the gastrointestinal tract. A 300-mg oral dose (5 mg/kg in children) achieves peak plasma concentrations of 3-5 mcg/mL within 1-2 hours. Isoniazid diffuses readily into all body fluids and tissues. The concentration in the central nervous system and cerebrospinal fluid ranges between 20% and 100% of simultaneous serum concentrations. 

Most tubercle bacilli are inhibited in vitro by ethionamide, 2.5 mcg/mL or less. Some other species of mycobacteria also are inhibited by ethionamide, 10 mcg/mL. Serum concentrations in plasma and tissues of approximately 20 mcg/mL are achieved by a dosage of 1 g/d. Cerebrospinal fluid concentrations are equal to those in serum. 

Foscarnet is available in an intravenous formulation only poor oral bioavailability and gastrointestinal intolerance preclude oral use. Cerebrospinal fluid concentrations are 43-67% of steady-state serum concentrations. Although the mean plasma half-life is 3-6.8 hours, up to 30% of foscarnet may be deposited in bone, with a half-life of several months. The clinical repercussions of this are unknown. Clearance of foscarnet is primarily renal and is directly proportional to creatinine clearance. Serum drug concentrations are reduced approximately 50% by hemodialysis. 

The thymidine analog stavudine (d4T) (Figure 49-2) has high oral bioavailability (86%) that is not food-dependent. The serum half-life is 1.1 hours, the intracellular half-life is 3.0-3.5 hours, and mean cerebrospinal fluid concentrations are 55% of those of plasma. Excretion is by active tubular secretion and glomerular filtration (Table 49-... 

Zalcitabine (ddC) is a cytosine analog with high oral bioavailability (87%) and a serum half-life of 1-2 hours. Intracellular half-life of 2.6 hours necessitates thrice-daily dosing, which limits its usefulness (Figure 49-2). Plasma levels decrease by 25-39% when the drug is administered with food or antacids. The drug is excreted renally. Cerebrospinal fluid concentrations are approximately 20% of those in the plasma. 

Praziquantel is a synthetic isoquinoline-pyrazine derivative. It is rapidly absorbed, with a bioavailability of about 80% after oral administration. Peak serum concentrations are reached 1-3 hours after a therapeutic dose. Cerebrospinal fluid concentrations of praziquantel reach 14-20% of the drug s plasma concentration. About 80% of the drug is bound to plasma proteins. Most of the drug is rapidly metabolized to inactive mono- and polyhydroxylated products after a first pass in the liver. The half-life is 0.8-1.5 hours. Excretion is mainly via the kidneys (60-80%) and bile (15-35%). Plasma concentrations of praziquantel increase when the drug is taken with a high-carbohydrate meal or with cimetidine bioavailability is markedly reduced with some antiepileptics (phenytoin, carbamazepine) or with corticosteroids. 

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