Cerebrospinal fluid, drug distribution

Kaddoumi, A., Choi, S.U., Kinman, L., Whittington, E., Tsai, C.C., Ho, R.J., Anderson, B.D., and Unadkat, J.D. (2007) Inhibition of P-glycoprotein activity at the primate blood-brain barrier increases the distribution of nelflnavir into the brain but not into the cerebrospinal fluid. Drug Metabolism and Disposition, 35, 1459-1462. 

Distribution - The therapeutic range for total serum chloramphenicol concentration is Peak, 10 to 20 mcg/mL trough, 5 to 10 mcg/mL. The drug is 60% bound to plasma proteins. Chloramphenicol enters the cerebrospinal fluid (CSF), even in the absence of meningeal inflammation. 

The drug is approximately 30% bound to plasma proteins. Ethionamide is rapidly and widely distributed into body tissues and fluids, with concentrations in plasma and various organs being approximately equal. Significant concentrations also are present in cerebrospinal fluid. 

The steady-state volume of distribution following IV administration of a 1.5 mg dose averaged 0.534 L/kg. Cerebrospinal fluid obtained from 9 patients at 2 to 3.5 hours following 0.06 or 0.09 mg/kg IV infusion showed measurable concentrations of zalcitabine. The CSFiplasma concentration ratio ranged from 9% to 37% (mean, 20%), demonstrating drug penetration through the blood-brain barrier. 

Mezlocillin, piperacillin, and ticarcillin are parenteral antibiotics formulated as sodium salts, so prescribers must consider the sodium content of these antibiotics when administering them to patients with congestive heart failure. During their distribution phase, antipseudomonal penicillins achieve orfly low concentrations in the cerebrospinal fluid. Consequently, antipseudomonal penicillins are not among the drugs of first choice for meningitis therapy. 

The pharmacokinetic properties of aztreonam are similar to those of the parenteral cephalosporins (Table 45.2). Aztreonam is not bioavailable after oral administration. During its distribution phase, the drug can achieve therapeutic concentrations in cerebrospinal fluid in the presence of inflamed meninges. Consequently, aztreonam is an alternative antibiotic to the cephalosporins for the therapy of meningitis caused by gram-negative bacilli. 

Orally administered ethambutol is well absorbed (70-80%) from the gut, and peak serum concentrations are obtained within 2 to 4 hours of drug administration it has a half-life of 3 to 4 hours. Ethambutol is widely distributed in all body fluids, including the cerebrospinal fluid, even in the absence of inflammation. A majority of the unchanged drug is excreted in the urine within 24 hours of ingestion. Up to 15% is excreted in the urine as an aldehyde and a dicarboxylic acid metabolite. Ethambutol doses may have to be modified in patients with renal failure. 

PAS is readily absorbed from the GI tract and is widely distributed throughout body fluids except cerebrospinal fluid. It penetrates tissues and reaches high concentrations in the tuberculous cavities and caseous tissue. Peak plasma levels are reached within 1 to 2 hours of drug administration, and the drug has a half-life of about an hour. PAS is primarily metabolized by hepatic acetylation. When combined with isoniazid, PAS can function as an alternative substrate and block hepatic acetylation of isoniazid, thereby increasing free isoniazid levels. Both the acetylated and unaltered drug are rapidly excreted in the urine. The concentration of PAS in urine is high and may result in crystalluria. 

Ethionamide is well absorbed foUowtng oral administration. It is rapidly and widely distributed to all body tissues and fluids, including the cerebrospinal fluid. Metabolism of ethionamide is extensive, and several dihydropyridine metabolites are produced. Less than 1% of the drug is eliminated in the urine unchanged. 

Absorption from the intestinal tract is usually good. Food delays but does not reduce absorption. The drug is distributed in body fluids and has a half-Ufe of about 8 hours. High levels are found in plasma and cerebrospinal fluid (CSF). Less than 20% binds to plasma proteins. Metronidazole is metabolized by oxidation and glucuronide formation in the liver and is primarily... 

The nitrosoureas are alkylating agents that are highly lipid soluble and share similar pharmacological and clinical properties. Carmustine (BCNU), lomustine (CCNU), and semustine (methyl-CCNU) are chemically unstable, forming highly reactive decomposition products. The chemical half-life of these drugs in plasma is only 5 to 15 minutes. Their marked lipid solubility facilitates distribution into the brain and cerebrospinal fluid (CSF). 

Vancomycin is poorly absorbed from the intestinal tract and is administered orally only for the treatment of antibiotic-associated enterocolitis caused by C difficile. Parenteral doses must be administered intravenously. A 1-hour intravenous infusion of 1 g produces blood levels of 15-30 mcg/mL for 1-2 hours. The drug is widely distributed in the body. Cerebrospinal fluid levels 7-30% of simultaneous serum concentrations are achieved if there is meningeal... 

The usual dosage of chloramphenicol is 50-100 mg/kg/d. After oral administration, crystalline chloramphenicol is rapidly and completely absorbed. A 1-g oral dose produces blood levels between 10 and 15 mcg/mL. Chloramphenicol palmitate is a prodrug that is hydrolyzed in the intestine to yield free chloramphenicol. The parenteral formulation is a prodrug, chloramphenicol succinate, which hydrolyzes to yield free chloramphenicol, giving blood levels somewhat lower than those achieved with orally administered drug. Chloramphenicol is widely distributed to virtually all tissues and body fluids, including the central nervous system and cerebrospinal fluid, such that the concentration of chloramphenicol in brain tissue may be equal to that in serum. The drug penetrates cell membranes readily. 

Trimethoprim is usually given orally, alone, or in combination with sulfamethoxazole, which has a similar half-life. Trimethoprim-sulfamethoxazole can also be given intravenously. Trimethoprim is well absorbed from the gut and distributed widely in body fluids and tissues, including cerebrospinal fluid. Because trimethoprim is more lipid-soluble than sulfamethoxazole, it has a larger volume of distribution than the latter drug. 

Tubercle bacilli are usually inhibited in vitro by aminosalicylic acid, 1-5 mcg/mL. Aminosalicylic acid is readily absorbed from the gastrointestinal tract. Serum levels are 50 mcg/mL or more after a 4-g oral dose. The dosage is 8-12 g/d orally for adults and 300 mg/kg/d for children. The drug is widely distributed in tissues and body fluids except the cerebrospinal fluid. Aminosalicylic acid is rapidly excreted in the urine, in part as active aminosalicylic acid and in part as the acetylated compound and other metabolic products. Very high concentrations of aminosalicylic acid are reached in the urine, which can result in crystalluria. 

Metronidazole is a nitroimidazole antiprotozoal drug (see Chapter 52) that also has potent antibacterial activity against anaerobes, including bacteroides and Clostridium species. It is well absorbed after oral administration, is widely distributed in tissues, and reaches serum levels of 4-6 mcg/mL after a 250-mg oral dose. Metronidazole can also be given intravenously or by rectal suppository. The drug penetrates well into the cerebrospinal fluid and brain, reaching levels similar to those in serum. Metronidazole is metabolized in the liver and may accumulate in hepatic insufficiency. 

Anesthesia of the lower extremities and abdomen may be induced by the introduction of anesthetic drugs into the subarachnoid space (Figure 23.6). The drug most often used for this purpose is bupivacaine. The latency period plus the duration of the maximal cephalad level for both plain and hyperbaric bupivacaine lasts from 10 to 60 min. A bupivacaine solution is made hyperbaric by the addition of 5 to 8% glucose. The distribution of bupivacaine in the cerebrospinal fluid (CSF) is affected by gravity and is therefore influenced by the patient s position. With a dose of 15 mg of plain 0.5% bupivacaine, a half-life of about 3 h is achieved. The addition of epinephrine to bupivacaine prolongs the duration of block. 

Zidovudine (azidothymidine AZT) is a deoxythymidine analog (Figure 49-4) that is well absorbed from the gut and distributed to most body tissues and fluids, including the cerebrospinal fluid, where drug levels are 60-65% of those in serum. Plasma protein binding is approximately 35%. 

Further studies have validated this hypothesis, in part,4 and ultimately this inventive premise was borne out in clinical practice. As a result, 5-FU (5) was eventually approved for treatment of solid tumors, such as breast, colorectal, and gastric cancers. Marketed as Adrucil when administered intravenously, 5-FU can be used either as monotherapy or combination therapy with various cytotoxic drugs and biochemical modulators, such as leucovorin and methotrexate.5 Because 5-fluorouracil is not orally bioavailable, it must be administered by continuous infusion to optimize its efficacy due to its short half-life in plasma. In addition, 5-FU has poor selectivity toward tumors in vivo, and its distribution into tissues such as bone marrow, the gastrointestinal tract, the liver and skin causes high incidences of toxicity. In addition, in spite of its limited lipid solubility, 5-fluorouracil diffuses readily across the blood-brain barrier into cerebrospinal fluid and brain tissue.1,5... 

The apparent volume of distribution of ciprofloxacin is 2-3.5 L/kg, and the apparent volume of distribution at steady state is 1.7-2.7 L/kg. Only low concentrations of ciprofloxacin are distributed into cerebrospinal fluid (CSF). Peak CSF concentrations may be 6-10% of peak serum concentrations. The drug is moderately bound to serum protein (16-43%), and crosses the placenta and is produced with the mammary milk [6, 10],... 

Distribution Sulfa drugs are distributed throughout body water and penetrate well into cerebrospinal fluid, even in the absence of inflammation. They can also pass the placental barrier and into breast milk. Sulfa drugs are bound to serum albumin in the circulation the extent of binding depends on the particular agent. 

Distribution Erythromycin distributes well to all body fluids except the cerebrospinal fluid (CSF). It is one of the few antibiotics that diffuses into prostatic fluid and has the unique characteristic of accumulating in macrophages. It concentrates in the liver. Inflammation allows for greater tissue penetration. Similarly, clarithromycin and azithromycin are widely distributed in tissues. Serum levels of azithromycin are low the drug is concentrated in neutrophils, macrophages, and fibroblasts. 

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