Lipophilic Character and Biological Activity of Drugs II: The Parabolic Case

Hansch, Corwin; Clayton, John M.

doi:10.1002/jps.2600620102

Cited by 346 publications

(86 citation statements)

References 95 publications

(11 reference statements)

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“…The octanol-water partition coefficient appeared to correlate somewhat better than the chloroform-water partition coefficient with the in vivo behavior of minocycline and doxycycline. Although the octanol-water system has been regarded as a good model for the study of passage across membranes, the relations involved are exceedingly complex and are best expressed logarithmically (13). We are, therefore, reluctant to draw any conclusion as to which type of partition coefficient correlates best with the pharmacological behavior of these agents.…”

Section: Discussionmentioning

confidence: 99%

Relation Between Lipophilicity and Pharmacological Behavior of Minocycline, Doxycycline, Tetracycline, and Oxytetracycline in Dogs

Barza

Brown

Shanks

et al. 1975

Antimicrob Agents Chemother

195

120

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Four tetracyclines were studied in dogs to determine the relation between their lipophilicity and various other pharmacological characteristics. Lipid solubility correlated inversely with the mean concentration of drug in arterial plasma and renal uptake and excretion, and directly with the biliary concentration gradient (level in bile/level of free drug in serum). Only the more lipophilic congeners minocycline and doxycycline passed the blood-brain and blood-ocular barriers in detectable concentrations. Mean levels of minocycline in the brain exceeded those of doxycycline by almost threefold; the difference was of borderline statistical significance (P = 0.05 to 0.1). Lipophilicity correlated inversely with the concentration of antibiotic in renal medulla but not in renal cortex or in the liver. When intestinal loops containing saline, milk, or 10% Gelusil were studied, the only combination exhibiting striking intraluminal accumulation was doxycycline in milk. These results indicate that lipophilicity correlates with many, but not all, of the transport characteristics of tetracycline antibiotics.Since the discovery of the tetracycline antibiotics over 25 years ago, a number of molecular modifications have been made with a view to improving tissue distribution, prolonging their half-life, augmenting intestinal absorption, and enhancing their antibacterial activity. Many of these objectives have been met in minocycline and doxycycline (6,9,10,25,26,34,41). Of additional interest is the fact that neither of these tetracyclines appears to require a major adjustment in dose in the presence of renal failure (6, 41), suggesting that they are extensively eliminated by nonrenal routes. Doxycycline has been demonstrated to be excreted extensively via the intestine (41). The data relative to minocycline, however, are inconclusive, and biliary excretion (29), intestinal excretion (6), and metabolic degradation (25) The purpose of the present investigation was to compare minocycline, doxycycline, tetracycline, and oxytetracycline with regard to their uptake and excretion by the liver and kidney, and their penetration into ileal contents, brain, cerebrospinal, and ocular fluids. The studies were carried out in a canine model that has been employed in previous investigations in our laboratory (5).MATERIALS AND METHODS Surgical preparation. The surgical preparation procedure has been described previously (5). Healthy mongrel dogs weighing 20 to 29 kg were anesthetized. Intravascular cannulas were placed in the femoral artery and vein and left renal, portal, and hepatic veins for aspiration of blood. Clotting was prevented by flushing the cannulas with heparin. Flow probes (Statham Co., Los Angeles, Calif.) were applied to the left renal and portal veins. Mean arterial pressure was recorded with a pressure transducer. Both ureters and the common bile duct were catheterized, and the cystic duct was ligated.Several additional procedures not performed in previous studies of this model were carried out. The terminal ileum was mobi...

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Section: Discussionmentioning

confidence: 99%

Relation Between Lipophilicity and Pharmacological Behavior of Minocycline, Doxycycline, Tetracycline, and Oxytetracycline in Dogs

Barza

Brown

Shanks

et al. 1975

Antimicrob Agents Chemother

195

120

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“…True td can be measured by using nonreplicating genetic markers or temperature-sensitive mutants (not multiplying in vivo) (5, 13, 80, 84a Growth limitation by different nutrients therefore gives rise to cells with reduced growth rates and coincidentally radically altered envelopes (6,10,28,46,59). This result has been widely reported to influence greatly susceptibility to antimicrobial agents (6,39) and to antibiotics (12,24,90) for a wide range of organisms (8,21,22,36,46,63,65,87 (42,96).…”

Section: Introductionmentioning

confidence: 99%

Influence of growth rate on susceptibility to antimicrobial agents: modification of the cell envelope and batch and continuous culture studies

Brown

Collier

Gilbert

1990

Antimicrob Agents Chemother

187

103

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“…The figure also shows that compounds of the present dataset have relatively higher log P values than compounds in the combined datasets of Wilschut et al (1995) and Flynn (1990). This follows the well established nonlinear relationship of biological activity with lipophilicity described by parabolic (Hansch and Clayton, 1973) or bilinear (Kubinyi, 1977) models. Compounds with extreme lipophilicity can be expected to partition into the skin and remain there, with little permeation to the aqueous receptor phase.…”

Section: Resultsmentioning

confidence: 84%

Modelling the effect of mixture components on permeation through skin

Ghafourian¹,

Samaras²,

Brooks³

et al. 2010

International Journal of Pharmaceutics

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A vehicle influences the concentration of penetrant within the membrane, affecting its diffusivity in the skin and rate of transport. Despite the huge amount of effort made for the understanding and modelling of the skin absorption of chemicals, a reliable estimation of the skin penetration potential from formulations remains a challenging objective. In this investigation, quantitative structure-activity relationship (QSAR) was employed to relate the skin permeation of compounds to the chemical properties of the mixture ingredients and the molecular structures of the penetrants. The skin permeability dataset consisted of permeability coefficients of 12 different penetrants each blended in 24 different solvent mixtures measured from finite-dose diffusion cell studies using porcine skin. Stepwise regression analysis resulted in a QSAR employing two penetrant descriptors and one solvent property. The penetrant descriptors were octanol/water partition coefficient, log P and the ninth order path molecular connectivity index, and the solvent property was the difference between boiling and melting points. The negative relationship between skin permeability coefficient and log P was attributed to the fact that most of the drugs in this particular dataset are extremely lipophilic in comparison with the compounds in the common skin permeability datasets used in QSAR. The findings show that compounds formulated in vehicles with small boiling and melting point gaps will be expected to have higher permeation through skin. The QSAR was validated internally, using a leave-many-out procedure, giving a mean absolute error of 0.396. The chemical space of the dataset was compared with that of the known skin permeability datasets and gaps were identified for future skin permeability measurements.

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Lipophilic Character and Biological Activity of Drugs II: The Parabolic Case

Cited by 346 publications

References 95 publications

Relation Between Lipophilicity and Pharmacological Behavior of Minocycline, Doxycycline, Tetracycline, and Oxytetracycline in Dogs

Relation Between Lipophilicity and Pharmacological Behavior of Minocycline, Doxycycline, Tetracycline, and Oxytetracycline in Dogs

Influence of growth rate on susceptibility to antimicrobial agents: modification of the cell envelope and batch and continuous culture studies

Modelling the effect of mixture components on permeation through skin

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