Cerebrospinal fluid, drug penetration

Prevendon of AIDS demenda by HAART does not depend on cerebrospinal fluid drug penetrance. AIDS Res Hum Redovi-ruses 20 483 91. 

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. 

Drug concentrations in pleural fluid, peritoneal fluid, synovial fluid, aqueous humor, and vitreous humor approach two-thirds of the serum concentration when local inflammation is present. Meningeal and am-niotic fluid penetration, with or without local inflammation, is uniformly poor. Measurement of serum, urine, or cerebrospinal fluid drug levels has not been used clinically. 

The importance of tissue penetration varies with the site of infection. The CNS is one body site where the importance of antimicrobial penetration is relatively well defined and correlations with clinical outcomes are established. Drugs that do not reach significant concentrations in cerebrospinal fluid should either be avoided or instilled directly when treating meningitis. 

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. 

Reductions in renal and hepatic function do not alter plasma drug concentrations, and ketoconazole is not removed by hemodialysis or peritoneal dialysis. Penetration into cerebrospinal fluid is negligible, so that ketoconazole is ineffective in the treatment of fungal meningitis. Since only small amounts of active drug appear in the urine, ketoconazole is not effective in the treatment of Candida cystitis. 

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. 

Although the terminal half-life of cidofovir is 2.6 hours, the active metabolite, cidofovir diphosphate, has a prolonged intracellular half-life of 17-65 hours, thus allowing infrequent dosing. A separate metabolite, cidofovir phosphocholine, has a half-life of at least 87 hours and may serve as an intracellular reservoir of active drug. Cerebrospinal fluid penetration is poor. Elimination is by active renal tubular secretion. High-flux hemodialysis has been shown to reduce the serum levels of cidofovir by approximately 75%. 

Indinavir requires an acidic environment for optimum solubility and therefore must be consumed on an empty stomach or with a small, low-fat, low-protein meal for maximal absorption (60-65%). The serum half-life is 1.5-2 hours, protein binding is approximately 60%, and the drug has a high level of cerebrospinal fluid penetration (up to 76% of serum levels). Excretion is primarily fecal. An increase in AUC by 60% and in half-life to 2.8 hours in the setting of hepatic insufficiency necessitates dose reduction. 

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. 

Carbapenems penetrate body tissues and fluids well, including the cerebrospinal fluid. All are cleared renally, and the dose must be reduced in patients with renal insufficiency. The usual dose of imipenem is 0.25-0.5 g given intravenously every 6-8 hours (half-life 1 hour). The usual adult dose of meropenem is 1 g intravenously every 8 hours. Ertapenem has the longest half-life (4 hours) and is administered as a once-daily dose of 1 g intravenously or intramuscularly. Intramuscular ertapenem is irritating, and for that reason the drug is formulated with 1% lidocaine for administration by this route. 

Callegari et al. characterized the central nervous system (CNS) penetration of the QTA trospium and methyl scopolamine as well as of the TTA scopolamine [77], Therefore, they performed in vivo studies administering the drugs to rats subcutaneously. After 1 h animals were euthanized, cerebrospinal fluid (CSF) was taken from cistema magna and brains were removed and homogenized. Whereas CSF was mixed with IS (atropine) to be directly injected for LC-ESI MS/MS analysis, brain homogenates were extracted by SPE on Oasis HLB material subsequent to IS... 

Blood-brain barrier Treatment of central nervous system infections, such as meningitis, depends on the ability of a drug to penetrate into the cerebrospinal fluid (CSF). The blood-brain barrier (see p. 8) ordinarily excludes many antibiotics. However, inflammation facilitates penetration and allows sufficient levels of many (but not all) antibiotics to enter the CSF. [Note For cure of meningitis, it is important that a bactericidal rather than a bacteriostatic effect is achieved in the CSF. Yet, this is not without its problems, since rapid bacteriolysis in the infected CSF will liberate high concentrations of bacterial cell walls and lipopolysaccharide that can exacerbate the inflammation. This has led to the use of adjunctive (simultaneous administration of) corticosteroids, which diminish the inflammatory process and neurologic sequelae.]... 

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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