Cerebrospinal fluid uptake and peripheral distribution of centrally acting drugs: Relation to lipid solubility

Ochs, Hermann R.; Greenblatt, David J.; Abernethy, Darrell R.; Arendt, R; Gerloff, J.; Eichelkraut, W.; Hahn, N

doi:10.1111/j.2042-7158.1985.tb03030.x

Cited by 33 publications

(29 citation statements)

References 27 publications

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“…Similarly, Pardridge has shown a correlation between lipophilicity and brain penetration of hormones [17]. Moreover, Ochs et al found that the rate of brain uptake of drugs was dependent on their lipophilicity [18]. The lipophilicity (log D) of salicylic acid, antipyrine, and amitriptyline was -0.9, 0.4, and 3.0, respectively, and the time required to reach the peak drug concentration in cerebrospinal fluid (CSF) after intravenous administration to dogs was 200, 34, and 4 min, respectively [18].…”

Section: Physicochemical Properties and Membrane Permeabilitymentioning

confidence: 96%

“…Moreover, Ochs et al found that the rate of brain uptake of drugs was dependent on their lipophilicity [18]. The lipophilicity (log D) of salicylic acid, antipyrine, and amitriptyline was -0.9, 0.4, and 3.0, respectively, and the time required to reach the peak drug concentration in cerebrospinal fluid (CSF) after intravenous administration to dogs was 200, 34, and 4 min, respectively [18]. However, a linear relationship between lipophilicity and membrane permeability can only be expected within a certain range.…”

Section: Physicochemical Properties and Membrane Permeabilitymentioning

confidence: 98%

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Tissue Distribution and Pharmacodynamics: A Complicated Relationship

Lin¹

2006

CDM

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With few exceptions, drugs exert their effects not within the plasma compartment, but in the defined target tissues. The process of drug distribution to the active site constitutes the "link-bridge" of the pharmacokinetic/pharmacodynamic (PK/PD) relationship. In spite of the importance of drug distribution as a key factor in determining pharmacologic response, research on drug distribution has historically received much less attention than that of absorption, metabolism, and excretion. The negligence of research on drug distribution is due mainly to the inaccessibility of the target tissues for obvious ethical reasons. In addition, lack of reliable experimental tools to assess the distribution process is also a major contributing factor. Because of this negligence, drug distribution has been referred to as "the forgotten relative in clinical pharmacokinetics." Although recent advances in molecular biology have led to the identification of many drug transporters, many of the processes of drug distribution are still not fully understood. The primary aim of this article is to provide new insight into the mechanisms of drug distribution, with an attempt to describe the relationship between the drug distribution and pharmacologic response. In addition, the factors that affect the processes of drug distribution will also be reviewed. Also, validity of some key assumptions that are used to relate the processes of tissue distribution with pharmacologic activity will be discussed.

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Section: Physicochemical Properties and Membrane Permeabilitymentioning

confidence: 96%

Section: Physicochemical Properties and Membrane Permeabilitymentioning

confidence: 98%

Tissue Distribution and Pharmacodynamics: A Complicated Relationship

Lin¹

2006

CDM

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“…As with previous studies of diazepam in the same species [12], flurazepam had high metabolic clearance averaging 37 ml/min/kg, and a short elimination half-life of 2.3 h. Like other lipophilic compounds [11], flura zepam was extensively distributed, with a mean volume of distribution of almost 8 1/kg. The only metabolite of flurazepam detected in serum was desalkylflurazepam, also a principal metabolite of flurazepam in humans [1,2,20,21], Other identified metabolic products of flurazepam were not measured in dog serum.…”

Section: Discussionmentioning

confidence: 51%

“…This experimental model has been utilized in previous studies to eval uate the serum pharmacokinetics, as well as the rate and extent of CSF entry, of a num ber of drug classes including benzodiaze pines, tricyclic antidepressants, neuroleptics, analgesics and antiarrhythmics [11][12][13], It is possible that the use of general anesthesia, which is necessary to allow cannulation of the CSF and repeated sampling from this site, could have altered the metabolic clear ance of the compounds evaluated in this and previous studies [ 13]. However, it is unlikely that anesthesia influenced peripheral tissue distribution and CSF entry, since these pro cesses appear to be governed by passive dis tribution.…”

Section: Discussionmentioning

confidence: 99%

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Pharmacokinetics and CSF Entry of Flurazepam in Dogs

et al. 1988

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Anesthetized dogs received a single 1.0-mg/kg intravenous dose of flurazepam hydrochloride, following which multiple blood and cerebrospinal fluid (CSF) samples were taken over the next 8 h. Concentrations of flurazepam and its metabolite, desalkylflurazepam, were determined by gas chromatography with electron-capture detection. Mean kinetic variables for flurazepam were: volume of distribution 7.9 1/kg, elimination half-life 2.3 h, clearance 37 ml/min/kg, serum free fraction 25% unbound. The metabolic product desalkylflurazepam appeared in serum in low concentrations, and was eliminated with a half-life of 4.9 h. Flurazepam rapidly entered CSF, then was eliminated in parallel with flurazepam in serum. However, the extent of entry into CSF was limited, with the mean ratio of area under the curve for CSF versus serum (0.24) nearly identical to the serum free fraction. Thus, intravenous flurazepam in dogs is characterized by extensive distribution, high clearance, and short half-life. Entry into CSF is rapid, and appears governed by passive diffusion. The extent of CSF entry is limited by protein binding in serum.

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Influence of age, gender, and obesity on salicylate kinetics following single doses of aspirin

Greenblatt

Abernethy

Boxenbaum

et al. 1986

Arthritis & Rheumatism

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Salicylate kinetics following single, 650-mg intravenous and oral doses of aspirin were evaluated in humans in 2 studies. Complete conversion of aspirin to salicylate was assumed. The first study involved 25 young (2540 years) and 21 elderly (66-89 years) healthy male and female volunteers. Mean salicylate clearance was lower in elderly females compared with that in young females; however, the difference between young men and elderly men was not significant. Salicylate free fraction in plasma increased significantly with age in men and women. After correction for free fraction, unbound mean clearance was reduced in elderly men compared with young men, and in elderly women compared with young women. Peak plasma salicylate concentrations after taking oral aspirin were not significantly influenced by age, and systemic availability of salicylate in all groups was complete. The second study compared 20 obese subjects (mean weight 113 kg) with 20 normal weight controls (mean weight 67 kg) matched for age, sex, height, and smoking habits. Small differences between obese and control groups were observed in total salicylate volume of distribution (vd), unbound Vd, and mean clearance of total or unbound salicylate. Following normalization for total weight, however, values of total Vd and mean clearance were significantly smaller in obese subjects than in normal weight subjects. Rate and completeness of salicylate absorption were not influenced by obesity when aspirin was ingested, although peak levels were lower in obese subjects. If applied to multiple doses, the reduced unbound clearance of salicylate in the elderly would imply increased accumulation unless doses are appropriately adjusted downward. During long-term therapy, salicylate dosage for obese individuals should not be adjusted upward in proportion to total weight.Aspirin is an extensively used antipyretic and analgesic agent that is available without prescription for the treatment of pain and inflammatory disorders. Following ingestion by humans, the parent compound is rapidly and quantitatively hydrolyzed to salicylate prior to, or shortly after, reaching the systemic circu- lation (1-3). The combined first-pass gut wall and hepatic metabolism of aspirin to salicylate has been estimated to be approximately one-third of an oral dose (4). Once in the systemic circulation, aspirin is rapidly hydrolyzed and has a disposition half-life of approximately 15 minutes (5).

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Cerebrospinal fluid uptake and peripheral distribution of centrally acting drugs: Relation to lipid solubility

Cited by 33 publications

References 27 publications

Tissue Distribution and Pharmacodynamics: A Complicated Relationship

Tissue Distribution and Pharmacodynamics: A Complicated Relationship

Pharmacokinetics and CSF Entry of Flurazepam in Dogs

Influence of age, gender, and obesity on salicylate kinetics following single doses of aspirin

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