Futile cycling between 4-methylumbelliferone and its sulfate and glucuronide conjugates was examined in the single-pass perfused rat liver preparation. The steady-state hepatic extraction ratio of 4-methylumbelliferone was found to be high (0.97) at a low input concentration of 0.005 mumol/L (tracer), with a net 4-methylumbelliferyl sulfate/4-methylumbelliferyl glucuronide ratio of about 5:1; at 63 mumol/L the steady-state extraction ratio had remained constant despite a shift from net sulfation to net glucuronidation. At higher input 4-methylumbelliferone concentrations, saturation was evidenced by a decreased steady-state extraction ratio and reduced net sulfation and net glucuronidation. Because 4-methylumbelliferyl sulfate and 4-methylumbelliferyl glucuronide deconjugation would result in an intracellular accumulation of 4-methylumbelliferone, the phenomenon was monitored with a shift in tracer [3H]4-methylumbelliferone metabolism from sulfation to glucuronidation with increased intracellular 4-methylumbelliferone concentration. When 4-methylumbelliferyl sulfate (0 to 890 mumol/L) or 4-methylumbelliferyl glucuronide (0 to 460 mumol/L) was delivered simultaneously with tracer [3H]4-methylumbelliferone to the rat liver, notable desulfation of 4-methylumbelliferyl sulfate (18% to 38% rate in) but little deglucuronidation of 4-methylumbelliferyl glucuronide (1.2% to 2.1% rate in) was observed. With 4-methylumbelliferyl sulfate, 4-methylumbelliferone and 4-methylumbelliferyl glucuronide were readily found as metabolites, whereas with 4-methylumbelliferyl glucuronide, levels of the metabolites, 4-methylumbelliferone and 4-methylumbelliferyl sulfate, were much reduced. 4-Methylumbelliferyl sulfate and not 4-methylumbelliferyl glucuronide shifted tracer [3H]4-methylumbelliferone metabolism from [3H]4-methylumbelliferyl sulfate to [3H]4-methylumbelliferyl glucuronide formation in a concentration-dependent fashion. The steady-state extraction ratio for 4-methylumbelliferyl sulfate (0.1 to 0.3) was comparatively higher than that for 4-methylumbelliferyl glucuronide (0.05), and it was found to increase with concentration, an observation explained by the nonlinear protein binding of 4-methylumbelliferyl sulfate. Biliary excretion rates for 4-methylumbelliferone and 4-methylumbelliferyl sulfate were proportional to their input or net formation rates, regardless of whether 4-methylumbelliferone, 4-methylumbelliferyl glucuronide or 4-methylumbelliferyl sulfate was administered. By contrast, the excretion rate of 4-methylumbelliferyl glucuronide when administered was only 1/25 the excretion of 4-methylumbelliferyl glucuronide formed from 4-methylumbelliferone and 4-methylumbelliferyl sulfate. The extent of choleresis paralleled the excretion patterns of preformed and formed 4-methylumbelliferyl glucuronide; bile flow was normal with 4-methylumbelliferyl glucuronide administration and was markedly enhanced with increased 4-methylumbelliferone or 4-methylumbelliferyl sulfate administration. The data suggest the presence of a tr...

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Inception and Background A1 Qaeda comes from the Arabic root qaf-ayn-dal. It can mean a base or a camp or a house, or a foundation, such as that which is under a house. It can mean a pedestal that supports a column. It can also mean a precept, rule, principle, maxim, formula, method, model or pattern. The word or phrase 'A1 Qaeda' was certainly in use in the mid 1980s among the Islamic radicals drawn from all over the Muslim world to fight the Soviets in Afghanistan alongside local resistance groups. For most of them it was used in a relatively mundane sense: to describe the base from which they operated. 1 However, the word 'A1 Qaeda' was also used by the most extreme elements among the radicals fighting in Afghanistan, particularly those who decided that their struggle did not end with the withdrawal of the Soviets from the country in 1989. Abdullah Azzam, the chief ideologue of the non-Afghan militants drawn to fight alongside the mujahideen and an early spiritual mentor of Osama bin Laden, a Saudi national and later leader of AJ Qaeda, used the word to describe the role he envisaged the most committed of the volunteers playing once the war against the Soviets was over. 2 In 1987, he wrote: "Every principle needs a vanguard to carry it forward and [to] put up with heavy tasks and enormous sacrifices. There is no ideology, neither earthly nor heavenly, that does not require...a vanguard that gives everything it possesses in order to achieve victory...It carries the flag all across the sheer, endless and difficult path until it reaches its destination in the reality of life, since Allah has destined that it should make and manifest itself. This vanguard constitutes the strong foundation or the expected society." 3 Osama bin Laden and a number of close-associates acted on Azzam's suggestion and sometime between 1988 and 1989 set up a militant group in Peshawar. To bin Laden's great distress, national and ethnic divisions reasserted themselves strongly among the volunteers. A1 Qaeda was formed with the express aim of overcoming these divisions and creating an 'international army', which would defend Muslims from oppression. The

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