One of the most important determinants of dermatological and systemic penetration after topical application is the delivery or flux of solutes into or through the skin. The maximum dose of solute able to be delivered over a given period of time and area of application is defined by its maximum flux (J(max), mol per cm(2) per h) from a given vehicle. In this work, J(max) values from aqueous solution across human skin were acquired or estimated from experimental data and correlated with solute physicochemical properties. Whereas epidermal permeability coefficients (k(p)) are optimally correlated to solute octanol-water partition coefficient (K(ow)) and molecular weight (MW) was found to be the dominant determinant of J(max) for this literature data set: log J(max)=-3.90-0.0190MW (n=87, r(2)=0.847, p<0.001). Estimated solubility in octanol (S(oc)) was also a determinant, but improvement in the regression by the addition of log S(oc) was small (r(2) increased to 0.856). Addition of other physicochemical parameters to MW by forward stepwise regression only marginally improved the regression with a melting point (Mpt) term (r(2)=0.879) and then hydrogen bonding acceptor capability (H(a)) (r(2)=0.917) is significant. Validation of the equation above was carried with a number of other data sets: an aqueous vehicle with full- and split-thickness skin (r(2)=0.784, n=56), some pure solutes (r(2)=0.537, n=34), an aqueous vehicle with ionizable solutes (r(2)=0.282, n=54) and solutes from a propylene glycol vehicle (r(2)=0.484, n=36). An analysis of the entire database gave the equation log J(max)=-4.52-0.0141MW (n=278, r(2)=0.688, p<0.001), with inclusion of Mpt and H(a) increasing r(2) to 0.760 (n=269). Separate analysis of full- and split-thickness skin data confirmed that the dermal resistance term had only a marginal effect on overall J(max). Application of the latter model to an in vivo situation where the dermal capillary bed is slightly below the epidermal-dermal junction revealed that the dermal resistance term was unnecessary for in vivo predictions for most solutes.
Enterohepatic recycling occurs by biliary excretion and intestinal reabsorption of a solute, sometimes with hepatic conjugation and intestinal deconjugation. Cycling is often associated with multiple peaks and a longer apparent half-life in a plasma concentration-time profile. Factors affecting biliary excretion include drug characteristics (chemical structure, polarity and molecular size), transport across sinusoidal plasma membrane and canniculae membranes, biotransformation and possible reabsorption from intrahepatic bile ductules. Intestinal reabsorption to complete the enterohepatic cycle may depend on hydrolysis of a drug conjugate by gut bacteria. Bioavailability is also affected by the extent of intestinal absorption, gut-wall P-glycoprotein efflux and gut-wall metabolism. Recently, there has been a considerable increase in our understanding of the role of transporters, of gene expression of intestinal and hepatic enzymes, and of hepatic zonation. Drugs, disease and genetics may result in induced or inhibited activity of transporters and metabolising enzymes. Reduced expression of one transporter, for example hepatic canalicular multidrug resistance-associated protein (MRP) 2, is often associated with enhanced expression of others, for example the usually quiescent basolateral efflux MRP3, to limit hepatic toxicity. In addition, physiologically relevant pharmacokinetic models, which describe enterohepatic recirculation in terms of its determinants (such as sporadic gall bladder emptying), have been developed. In general, enterohepatic recirculation may prolong the pharmacological effect of certain drugs and drug metabolites. Of particular importance is the potential amplifying effect of enterohepatic variability in defining differences in the bioavailability, apparent volume of distribution and clearance of a given compound. Genetic abnormalities, disease states, orally administered adsorbents and certain coadministered drugs all affect enterohepatic recycling.
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