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The purpose of this investigation was to determine the suitability of orally administered magnesium sulfate as a source of inorganic sulfate for counteracting the systemic depletion of sulfate caused by large doses of acetaminophen and certain other drugs that are metabolized to sulfate conjugates. Oral administration of 13.9 g magnesium sulfate U.S.P., in 4 equal hourly increments, to seven healthy men resulted in the urinary excretion (corrected for baseline excretion rate) of an amount of inorganic sulfate equivalent to 30.2 +/- 17.2 percent (mean +/- SD) of the dose during the first 24 hours. Excretion during the subsequent 48 hours was negligible. Six of the subjects experienced loose stools or diarrhea. Compared to sodium sulfate, magnesium sulfate appears to be absorbed less completely and more erratically, and to produce more adverse effects.

Salicylamide (SAM) can produce sedation and sleep in humans and animals. To explore the potential utility of the drug as a research tool for assessing disease effects on the response of the central nervous system to depressant drugs, and to obtain a better understanding of the clinically evident sedative action of SAM, studies were performed to characterize the relationship between the concentrations and hypnotic effect of this drug in rats. Female Lewis rats weighing 170–200 g received SAM by intravenous infusion at a rate of 0.49, 1.22, or 2.47 mg/min until the onset of loss of the righting reflex. This well-defined pharmacological endpoint occurred from 16.7 ± 2.3 min (fastest infusion rate) to 110 ± 27 min (slowest infusion rate) after the start of the infusion. SAM concentrations at that time in serum, serum water, brain, and cerebrospinal fluid (CSF) were similar in animals that had received the 1.22- or 2.47-mg/min infusion and lower in animals that were infused at a rate of 0.49 mg/min. The slowest infusion rate group also exhibited increased serum protein binding of the drug. The SAM concentration ratio, CSF–serum water, was essentially unity in all three groups, indicative of rapid equilibration of the drug across the blood–CSF barrier. Gentisamide, the hydroxylated metabolite of SAM, was found in serum, CSF, and brain, but in low concentrations at which this metabolite alone had no hypnotic effect. When SAM was infused for some time beyond the onset of loss of the righting reflex, concentrations of the drug in serum, CSF, and the brain at recovery of the righting reflex were somewhat higher than at onset of loss of the righting reflex. The results of this investigation suggest that SAM exerts a direct effect on the central nervous sytem and that its hypnotic activity may be subject to development of acute tolerance.

Little is known regarding the biotransformation of drugs in Down's syndrome. In particular, there are no published studies that examine metabolic pathways such as N-acetylation, which can exhibit genetically-determined variability. The objective of the present investigation was to compare the acetylator phenotypes of white subjects with Down's syndrome with age-matched control subjects, with use of caffeine as the pharmacologic probe. After the ingestion of caffeine-containing beverages, spot urine collections were obtained at 2 and 4 hours in 22 subjects with Down's syndrome and in 22 control subjects (age range of 4 to 49 years). The urinary excretion ratios of 5-acetylamino-6-amino-3-methyluracil (AAMU) to 1-methylxanthine (1X) determined in these 2-hour and 4-hour samples were highly correlated (r = 0.82; p < 0.001). In addition, more extensive urinary excretion studies performed for an 8-hour period in three subjects with Down's syndrome demonstrated that the coefficient of variability for the ratio of AAMU/1X ranged from 10.1% to 14.2%, which is similar to the reproducibility previously reported for control subjects. A trimodal distribution of acetylator phenotypes was observed, with no differences in average or frequency distribution of ratio values between the subjects with Down's syndrome and the control subjects. This study demonstrates that polymorphic N-acetylator status, as assessed by caffeine metabolism, is similar in subjects with Down's syndrome and in control subjects. Clinical Pharmacology and Therapeutics (1989) 46, 359–366; doi:10.1038/clpt.1989.151

Two high-performance liquid chromatographic (HPLC) assay procedures were developed for the determination of salicylamide and its metabolites in serum, urine, and saliva. One method involves reverse-phase ion-pair chromatography and UV detection, and is used to determine salicylamide, salicylamide glucuronide, and salicylamide sulfate. The other method, with a different mobile phase and without the ion-pairing reagent, is used to determine gentisamide (the hydroxylated metabolite of salicylamide), gentisamide glucuronide, and gentisamide sulfate. The assays are performed by direct injection of the sample after protein precipitation with ethanol containing the internal standard. Increased sensitivity for the determination of low concentrations of salicylamide is obtained by organic extraction of this drug from serum or saliva. Calibration curves for the conjugates of salicylamide and gentisamide were obtained, in the absence of authentic standards, by partial enzymatic hydrolysis, using the decrease of the conjugate peaks and the concomitant increase of free salicylamide or gentisamide concentrations to determine peak area ratio–concentration relationships. Application of the HPLC assay procedures to the determination of salicylamide excretion products in the urine of three normal human subjects resulted in 98.6% (range: 97.1–100.1%) recovery of a 1-g oral dose of the drug. All five metabolites of salicylamide were found in urine, but only salicylamide glucuronide, salicylamide sulfate, and gentisamide glucuronide were found consistently and in appreciable quantities. Salicylamide and all of its metabolites except gentisamide sulfate were found in human and rat serum, and unconjugated salicylamide as well as gentisamide were found in human saliva.

Modulating effects of competing pathways, exemplified by sulfation (high affinity-low capacity) and glucuronidation (low affinity-high capacity), on drug disappearance and metabolite formation were investigated in a simulation study. The phenomenon of substrate recruitment of hepatocyte activity in drug removal and metabolite formation was shown with respect to inlet substrate concentration, and drug processing from inlet to outlet by enzyme systems localized differentially along the sinusoidal flow path in liver. Three enzymic distribution models: (A) sulfation and glucuronidation evenly distributed in liver, (b) sulfation occurring exclusively in the first half of the liver and glucuronidation in the second half, and (C) glucuronidation solely in the first half and sulfation in the second half, were described. The influence of Kmand Vmax of the competing pathway, including enzyme induction (increase in Vmax), on any given pathway was also explored. Competing pathways exert their effects on other given pathways by modulating intrahepatic drug concentration from the inlet to outlet of the liver. When a competing pathway is similarly distributed or is at an anterior location to another pathway, the former pathway effectively reduces intrahepatic drug concentrations which reach downstream hepatocytes for recruitment of activity. For example, when glucuronidation activity is anterior to sulfation activity (defined with respect to flow direction), sulfation is without an effect on glucuronidation, but glucuronidation exerts a maximal influence over sulfation rates (Model C). When glucuronidation is in direct competition with sulfation (Model A) or is posteriorly distributed to sulfation (Model B), saturation of the high-affinity sulfation pathway leads to greater fluxes of substrate available downstream for glucuronidation. This results in an apparent compensatory increase in glucuronidation with reduced sulfation capacity, which occurs at input concentrations greater than the Km for sulfation but less than the Km for glucuronidation. This compensation pattern is more prominent for highly extracted compounds where both sulfation and glucoronidation are effective pathways in drug removal, and where large intrahepatic drug concentration gradients are expected. Since the physiologic description of intraheptic drug concentration is often described by a concentration gradient from the inlet to outlet of the liver, the logarithmic average concentration has been used to estimate the mean liver concentration in the determination of kinetic constants for enzymic reactions. The appropriateness of the method for competing pathways is presently assessed for four phenolic substrates: 1-naphthol, acetaminophen, harmol, and salicylamide, compounds listed in order of increasing extraction ratios. By employing published values for the enzymatic constants, the simulated sulfation and glucuronidation rates, accordingly for the three cases A, B, and C, and the logarithmic concentrations were refitted to the Michaelis-Menten equation. A comparison of the assigned and fitted kinetic constants revealed that for case A, the enzymatic constants agreed well for both sulfation and glucuronidation. For cases B and C of unevenly distributed enzymes, the fitted enzymatic constants for sulfation, the high-affinity pathway, were in good agreement with assigned values. Those for the low affinity, glucuronidation pathways, however, differed for the highly cleared drugs harmol and salicylamide, and for acetaminophen, for which glucuronidation is a very poor metabolic pathway. But for 1-naphthol, where the assigned Km's as well as the Vmax's for sulfation and glucuronidation are similar, reasonably good agreement between the fitted and assigned enzymatic constants was obtained. These differential observations for competing pathways are explained by the perturbation of intrahepatic concentrations and the phenomenon of substrate recruitment of hepatocyte activities, for poorly or highly extracted compounds.

The renal clearances of acetaminophen, acetaminophen glucuronide, and acetaminophen sulfate were determined in eight healthy adults 2 h after administration of 1.5 g of acetaminophen. The renal clearance ratios (relative to creatinine) were 0.058 +/- 0.026, 0.890 +/- 0.153, and 1.43 +/- 0.250 (mean +/- SD), respectively. The renal clearance of acetaminophen increased with increasing urine flow rate, and that of acetaminophen sulfate decreased with increasing serum concentration of the conjugate. A strong positive correlation was found between the renal clearances of acetaminophen glucuronide and acetaminophen sulfate, possibly due to blood perfusion rate-dependent renal tubular secretion of the two conjugates. The serum protein binding of acetaminophen (congruent to 20%) and acetaminophen glucuronide (less than 10%) are minor. Acetaminophen sulfate is greater than 50% protein bound, as determined by equilibrium dialysis and ultrafiltration. The results of these studies are (a) consistent with previous reports of animal studies, indicating that renal excretion of acetaminophen involves glomerular filtration and passive reabsorption and that acetaminophen sulfate is subject to active renal tubular secretion, and (b) compatible with the reported occurrence of renal tubular secretion of acetaminophen glucuronide in animals.

The American Association of Pharmaceutical Scientists (AAPS) covers the full range of areas of expertise associated with the resolution of concerns pertaining to drugs and drug products. This editorial highlights the initiatives, issues, and challenges that are the forefront of the pharmaceutical sciences in 2007. It also provides an overview of how these difficult questions are being addressed through the programs and events associated with the AAPS 2007 Annual Meeting that will be held at the San Diego, California, Convention Center from November 11 to 15, 2007.