Hepatic encephalopathy and altered cimetidine kinetics.

Cimetidine kinetics were followed in 16 cirrhotic patients after a single IV 300-mg dose. The patients were grouped according to a history of portal systemic encephalopathy (PSE). There were no differences among the groups in volume of distribution, biologic t 1/2, or distributional clearance. In cirrhotic patients with no history of PSE, cimetidine kinetics and metabolism were the same as in healthy subjects. Patients with a history of PSE (n = 8) had lower cimetidine total body clearance than cirrhotic patients without a history of PSE and healthy subjects. Cirrhotic patients with a history of PSE also had decreased formation of cimetidine sulfoxide (as judged by differences in the sulfoxide serum concentration-time AUC). Because of the 40% decrease in total clearance, dosage in cirrhotic patients with a history of PSE should be reduced to minimize the risk of CNS side effects associated with cimetidine.

The effect of acetaminophen on the disposition of fenoldopam: competition for sulfation.

Both fenoldopam and acetaminophen undergo conjugation with sulfate in humans. The present study was undertaken to determine if a metabolic interaction exists between these two compounds in humans. Twelve healthy male volunteers participated in a single-dose crossover study with 100 mg fenoldopam (capsule) alone or in combination with 1000 mg acetaminophen. The effects of chronic acetaminophen dosing (1000 mg three times/day for 7 days) on a single 100 mg tablet of fenoldopam were studied in a second crossover study in seven additional volunteers. Concomitant dosing with fenoldopam with acetaminophen resulted in increases in peak fenoldopam plasma concentration and AUC after both single (+32% and +50%, respectively) and chronic (+73% and +66%, respectively) acetaminophen dosing. Decreases in peak plasma concentrations and AUC for fenoldopam's sulfated metabolites were seen in both studies. These findings indicate a metabolic basis for the interaction between fenoldopam and acetaminophen, presumably through a competition for inorganic sulfate.

The effect of fenoldopam, a dopaminergic agonist, on renal hemodynamics.

Fenoldopam, a dopaminergic agonist, was administered intravenously to 18 healthy male subjects in doses ranging from 0.025 to 1.0 microgram/kg/min for 2 hours. Three subjects were studied in a three-way crossover of fenoldopam at doses of 0.025, 0.10, and 0.50 microgram/kg/min. Fenoldopam decreased diastolic blood pressure and increased pulse rate without changing systolic blood pressure. Fenoldopam produced dose-related increases in para-aminohippuric acid clearance up to 75% at the 0.50 microgram/kg/min dose. This increase in renal blood flow was accompanied by increases in urine volume, water, and solute excretion; glomerular filtration rate was unchanged. Doses greater than 0.25 microgram/kg/min caused flushing and nasal congestion. The dopamine receptor antagonist metoclopramide (0.1 mg/kg/hr) did not block the systemic hemodynamic effects of fenoldopam but attenuated the increase in para-aminohippuric acid clearance. Fenoldopam plasma levels achieved steady state between 30 and 120 minutes after the start of the infusion and were linear with respect to infusion rate. Our findings show that intravenous fenoldopam causes systemic arteriolar vasodilation, accompanied by renal vasodilation and increased sodium excretion.

Cimetidine kinetics during resuscitation from burn shock.

Severely burned patients suffer from rapidly changing metabolic and hemodynamic abnormalities that could alter drug kinetics. The kinetics of cimetidine, commonly used in the prophylaxis of acute stress erosions, were studied during fluid resuscitation of 11 patients with mean burn sizes of 45% total body surface area. Six patients were studied after the completion of fluid resuscitation. Total clearance, steady-state volume of distribution, and cimetidine t1/2 did not change between the early period after burn and after fluid resuscitation, but before the completion of fluid resuscitation patients had lower renal and greater nonrenal cimetidine clearance than after resuscitation. The increase in nonrenal cimetidine clearance resulted in decreased urinary recovery of unchanged drug, 50.7 +/- 14% during fluid resuscitation and 81.0% +/- 6% after resuscitation.

Ranitidine disposition and systemic availability in hepatic cirrhosis.

Single-dose ranitidine kinetics were studied in 10 patients with cirrhosis as proved by liver biopsy. All were clinically stable. After an overnight fast, ranitidine was given in a randomized crossover order as a bolus intravenous injection (50 mg) or was taken by mouth (150 mg). Terminal t1/2 was 2.7 +/- 0.4 hr after oral dosing and 2.9 +/- 0.4 hr after intravenous injection. Total plasma clearance was 470 +/- 170 ml/min and the steady-state volume of distribution was 1.2 +/- 0.2 l/kg. There was considerable intersubject variability in the ranitidine serum concentration-time profile after oral dosing. Systemic availability as assessed by AUC analysis was 58% +/- 11%. Not all of the dose could be recovered in the urine as unchanged ranitidine and its known metabolites after intravenous injection. At 0.5 microgram/ml the serum protein binding of ranitidine was 4.6% +/- 1.3%. It is concluded that disposition of ranitidine in these 10 stable subjects with cirrhosis was not significantly altered. The minor changes observed in some were as likely to be the result of secondary perturbations in physiologic status as to effects of cirrhosis on drug metabolism.

Design, synthesis, and biological evaluation of conformationally constrained aci-reductone mimics of arachidonic acid.

An efficient and convergent synthesis has been developed for the production of 3,4-dihydroxy-5-[4-(2-((2Z)-hexenyl)phenyl)-3-(1Z)-but enyl]-2 (5H)-furanone (12d). This hydrophobic antioxidant is a stable conformationally constrained mimic of arachidonic acid (AA) (1) and its respective aci-reductone analogue (2). Pd(0)-catalyzed cross-coupling of 5-(3-butynyl)-3,4-dihydroxy-2(5H)-furanone (7) with 2-((2Z)-hexenyl)iodobenzene (8d) followed by Lindlar catalyzed hydrogenation produces 12d. Butynyl intermediate 7 is prepared from 2-(benzyloxy)-5-deoxyascorbic acid (15) by iodination (I2, PPh3, Imd), iodo substitution with lithium acetylide ethylenediamine complex (LiAEDA, HMPA, -5 degrees C), and benzyl group cleavage (Ac2O, Pyr, BCl3). The utility of this synthetic method was demonstrated by the synthesis of analogues 10e-k. Biological testing revealed that certain of these antioxidants inhibit both cyclooxygenase (COX) and 5-lipoxygenase (5-LO) with comparable efficacy as reported for aspirin and zileuton, respectively. The antioxidant activity of these aci-reductones, measured as a function of their inhibitory effect on CCl4-induced lipid peroxidation of hepatic microsomes, exceeds that produced by alpha-tocopherol. Synthetic routes and initial structure-activity relationships (SAR) for these novel mixed functioning antioxidants are presented.

Transport of celiprolol across human intestinal epithelial (Caco-2) cells: mediation of secretion by multiple transporters including P-glycoprotein.

1. The transepithelial transport of the beta-adrenoceptor blocking drug, celiprolol, was investigated in monolayers of the well differentiated human intestinal epithelial cell line, Caco-2. 2. The basal-to-apical transport (secretion) of [14C]-celiprolol (50 microM) was 5 times higher than apical-to-basal transport (absorption). In the presence of an excess (5 mM) of unlabelled celiprolol the basal-to-apical transport was reduced by more than 80%, whereas the apical-to-basal transport remained unchanged. 3. Net celiprolol secretion obtained in the concentration range 0.01 to 5 mM displayed saturable kinetics with an apparent Km of 1.00 +/- 0.23 mM and Vmax of 113 +/- 11 pmol/10(6) cells min-1. These results are consistent with saturable active secretion and provide an explanation for the dose-dependent bioavailability of celiprolol. 4. The secretion of celiprolol was sensitive to pH, and decreased in the absence of sodium and in the presence of ouabain, suggesting that transport was coupled to proton and sodium gradients. 5. The secretion of celiprolol was inhibited by substrates for P-glycoprotein (vinblastine, verapamil and nifedipine) and either inhibited or stimulated by typical substrates for the renal organic cation-H+ exchanger (cimetidine, N1-methylnicotinamide, tetraethylammonium and choline), suggesting that there are at least two distinct transport systems. 6. The secretion of celiprolol was also inhibited by other beta-adrenoceptor blocking drugs (acebutolol, atenolol, metoprolol, pafenolol and propranolol) and by the diuretics, acetazolamide, chlorthalidone and hydrochlorothiazide, suggesting that the clinically observed effect of chlorthalidone on the bioavailability of celiprolol occurs at the level of the intestinal epithelium.

Potent inhibitory activities of hydrophobic aci-reductones (2-hydroxytetronic acid analogs) against membrane and human low-density lipoprotein oxidation.

The effects of selected aci-reductones, which are hydrophobic ascorbate-related analogs including 4-chlorophenyl-2-hydroxytetronic acid (Cpd A), 4-(1,1'-biphenyl)-2-hydroxytetronic acid (Cpd B), and 4-(4'-chloro-1,1'-biphenyl)-2-hydroxytetronic acid (Cpd C), on membrane and low density lipoprotein (LDL) oxidation were assessed. Hepatic microsomal lipid peroxidation was induced by the ascorbate + Fe(II) chemical system. All three agents inhibited membrane lipid peroxidation in a concentration-dependent manner with the order of potency: Trolox (vitamin E) < or = Cpd A << Cpd B < Cpd C; based on the EC50 values, Cpd B and Cpd C were 11- and 19-fold, respectively, more potent than Trolox. In contrast to ascorbic acid, all three agents did not display any membrane prooxidative effect in the presence of iron. When human LDL was incubated with 10 microM of Cu(II), LDL oxidation, determined by the formation of thiobarbituric acid reactive substances, followed a typical sigmoidal curve with an initial lag phase. Preincubation of the LDL samples with low micromolar concentrations (1 and 3 microM) of each agents for 30 min before the addition of copper resulted in significant delays of the lag time of LDL oxidation, and the effectiveness of Cpd B and Cpd C was more prominent than that mediated by either Trolox or probucol. Since clinical evidence strongly supports the hypothesis that atherogenesis is initiated by LDL oxidation, the results suggest that these aryl tetronic acid analogs may serve as promising candidates for future therapeutic use as anti-atherogenic agents.

Nasal mucosal inflammation has no effect on the absorption of intranasal triamcinolone acetonide.

The potential for enhanced systemic absorption of intranasal triamcinolone acetonide was explored in patients with inflamed nasal mucosa. Twelve allergic rhinitis patients with documented nasal inflammation, and 12 healthy volunteers, each received a single, therapeutic, 400-micrograms dose of triamcinolone acetonide in each nostril. Blood was obtained at fixed time points after the dose, and plasma concentrations of triamcinolone acetonide were determined by radioimmunoassay. There were no statistically significant differences in any of the derived pharmacokinetic parameters (maximum plasma triamcinolone acetonide concentrations [Cmax], time to maximum plasma triamcinolone concentrations [Tmax], elimination half-life [t1/2], and area under the plasma concentration-time curve [AUC0-12] from 0 to 12 hours) between treatment groups. A once-a-day, chronic regimen (6 weeks) of triamcinolone acetonide was also administered to five patients with allergic rhinitis. Pharmacokinetic parameters were similar to the parameters derived from healthy volunteers after acute administration. There was no evidence of drug accumulation. The results of this study indicate that acute and chronic intranasal administration. The results of this study indicate that acute and chronic intranasal administration of therapeutic doses of triamcinolone acetonide to patients with inflamed nasal mucosa does not result in enhanced systemic drug absorption or accumulation.

Inhaled corticosteroids in asthma: a dose-proportionality study with triamcinolone acetonide aerosol.

The systemic exposure to triamcinolone acetonide (TAA) after inhalation of aerosolized drug has not been examined previously. This study evaluates the plasma concentrations, pharmacokinetics and dose proportionality of TAA after single oral inhalations at doses of 400, 800, and 1600 mcg. Nine moderately asthmatic male patients received each of the doses in a randomized crossover manner using a 1-week washout period between dosing. Serial blood samples were collected for 10 hours postdosing for the determination of plasma TAA concentrations by using a specific radioimmunoassay. The pharmacokinetic profiles that were obtained showed slow and limited absorption over the first 4 hours after dosing followed by rapid elimination with a half-life of approximately 2 hours (range: 1.8-2.3 hr). Comparison of pharmacokinetic parameters from each dose group showed excellent proportionality and consistent absorption for all patients. Mean Cmax values ranged from 0.51 ng/mL after the 400 mcg dose to 1.01 ng/mL and 1.97 ng/mL after the 800 and 1600 mcg doses, respectively. Mean AUC0-10 values for these same doses were 2.6 ng x hr/mL, 5.3 ng x hr/mL and 10.5 ng x hr/mL, respectively. The results suggest that systemic exposure to TAA is minimal after oral inhalation, occurs in a dose proportional fashion, and produces circulating plasma concentrations which are unlikely to have significant adverse systemic effects.

Steady-state dose proportionality of a once-a-day sustained-release diltiazem hydrochloride formulation in healthy subjects.

In this open-label, randomized, cross-over study, 12 healthy subjects received four doses of a new sustained-release formulation of diltiazem hydrochloride for six consecutive days. Blood samples were drawn on days 5 and 6 for determination of plasma diltiazem and desacetyldiltiazem levels. The peak concentrations after 120, 240, 360, and 480 mg of diltiazem were 48.1, 112.6, 180.9, and 276.8 ng/ml, respectively, while the mean minimum concentrations were 6.3, 14.6, 24.9, and 44.6 ng/ml. The areas under the concentration-time curves were 702, 1,642, 2,622, and 4,004 ng.hr/ml. Prolonged, continuous absorption of diltiazem was noted over the 24-hour dosing period. The dose-adjusted mean steady-state plasma diltiazem levels after the four doses were significantly different, consistent with diltiazem's nonlinear absorption, but the plasma profiles were similar, indicating that the diltiazem release rate was not dose-dependent. Therapeutic plasma diltiazem levels (greater than or equal to 40 ng/ml) were maintained for 24 hours after the three larger doses. The changes in the pharmacokinetics of desacetyldiltiazem over the four diltiazem doses were similar to those of diltiazem. The number of adverse treatment experiences tended to increase with the higher doses, but none were severe. The results indicate that, according to their pharmacokinetic profiles, doses of 240 mg to 480 mg of diltiazem are suitable for once-daily administration.

Multicenter evaluation of the efficacy and safety of sustained-release diltiazem hydrochloride for the treatment of hypertension.

In a double-blind study, patients with mild-to-moderate hypertension were randomly assigned to receive placebo or increasing daily doses of a new sustained-release formulation of diltiazem: 180 mg, 360 mg, and 540 mg, each once daily for two weeks. The numbers of evaluable patients were 26 in the placebo group and 81 in the diltiazem group at week 2, 24 and 75 at week 4, and 23 and 65 at week 6. Changes from baseline in mean supine trough (before drug administration) systolic/diastolic blood pressures were +1.3/-2.7 mmHg after placebo and -4.7/-6.1 mmHg after diltiazem at week 2; -0.1/-1.7 mmHg after placebo and -7.2/-9.3 mmHg after diltiazem at week 4; and +0.4/-1.7 mmHg after placebo and -6.7/-10.2 mmHg after diltiazem at week 6. The changes were significantly greater after diltiazem than placebo. Increasing the daily dose of diltiazem from 360 mg to 540 mg produced more than proportional increases in mean plasma diltiazem concentrations but only minimal further reductions in blood pressure. Similar rates of adverse experiences were reported by the diltiazem-treated and placebo patients. Treatment was withdrawn in two diltiazem-treated patients because of abnormal electrocardiographic (ECG) changes that were considered to be related to the drug: elevated ST segment in one and first-degree atrioventricular block in the other. No other treatment-related ECG changes were noted. It is concluded that this new once-daily formulation of diltiazem is safe and effective in the treatment of mild-to-moderate hypertension.

Mental confusion in a patient treated with metronidazole--a concentration-related effect?

We report a case of serious mental confusion, hallucinations, and agitation in a 65 year old man, occurring in close relationship to the intravenous administration of metronidazole. The patient was treated twice, but at different dosages. The confusion and hallucinations occurred at the recommended daily dose of 2.0 g, but did not return at a daily dose of 500 mg. Metronidazole serum concentrations were obtained throughout both courses of therapy; CSF and tissue concentrations were obtained at autopsy. The mental confusion was associated with peak serum concentrations of approximately 40 micrograms/ml. Symptoms resolved within 24-48 hr after stopping metronidazole, and resolution was consistent with a metronidazole half life of 14 hr. We conclude that metronidazole can be associated with a dose- and serum concentration-related mental confusion state, and that this side effect appears completely reversible upon discontinuing the drug.

Immobilized sulfatase:beta-glucuronidase enzymes for the qualitative and quantitative analysis of drug conjugates.

The enzymes sulfatase and beta-glucuronidase from Helix pomatia were simultaneously immobilized on aminopropyl control pore glass. Once immobilized, these enzymes retained activity under varied conditions of pH, organic solvent, and temperature. To hydrolyze the sulfate and glucuronide conjugates of xenobiotics, the immobilized enzymes were either added directly to incubation mixtures for qualitative in vitro studies or packed in a short stainless steel column and placed in an HPLC system for quantitative studies. By incorporating specific inhibitors (D-saccharic acid-1,4-lactone to inhibit beta-glucuronidase or phosphate ions to inhibit sulfatase) into the incubation mixture or into the HPLC mobile phases, selective hydrolysis of either sulfate or glucuronide conjugates was achieved. Upon removal of the inhibitors from the incubation mixtures or from the mobile phases, original enzyme activity was restored. The utility of immobilized enzymes was demonstrated for quantitative analysis of sulfate and glucuronide conjugates of fenoldopam, where the liberation of the catechol aglycone moiety was necessary for electrochemical detection.

HPLC determination of D and L moxalactam in human serum and urine.

A high-pressure liquid chromatographic procedure was developed to determine the D and L isomers of moxalactam in human plasma and urine. After protein precipitation with hydrochloric acid the sample was extracted with ethyl acetate. It was then back extracted into tromethamine buffer (pH 8.0) and washed with octanol. Extraction recovery from plasma ranged from 73-81%. An aliquot of the tromethamine buffer was then injected onto a C18-muBondapak column. The mobile phase was 3% acetonitrile in 0.05 M ammonium acetate pH 6.5 buffer. Samples were quantitated by UV detection at 275 nm and 0.01 aufs. The lower limit of detection was 0.5 microgram/ml for each isomer. Preliminary stability studies were performed to assess proper sample handling and storage conditions. The procedure was evaluated in a clinical setting to demonstrate its applicability to the study of moxalactam pharmacokinetics in critically ill patients.

Liquid-chromatographic determination of cimetidine, its known metabolites, and creatinine in serum and urine.

We describe a liquid-chromatographic procedure for determination of cimetidine, its hydroxymethyl-, sulfoxide-, and guanyl urea metabolites, and creatinine in patients serum and urine. SKF 92374 is used as the internal standard. Protein in 0.5 mL of serum or diluted urine is precipitated with 2 mL of acetonitrile, the organic and aqueous phases are separated by adding 0.3-0.5 g of anhydrous K2HPO4. The organic phase is evaporated, and 0.5 mL of 50 mmol/L HCl is added. This solution is washed with 3 mL of water-saturated isoamyl alcohol, the aqueous phase is extracted with 3 mL of methylene chloride and enough K2HPO4 to saturate the solution. The methylene chloride is evaporated, the residue reconstituted with 100 microL of mobile phase, and a 25-microL aliquot injected onto the chromatographic column (Dupont Sil). The mobile phase is acetonitrile/methanol/water/ammonium hydroxide (1000/50/50/2, by vol). The column effluent is monitored at 228 nm. Lower limits of detection ranged from 0.05 mg/L for cimetidine to 0.2 mg/L for guanyl urea. We determined cimetidine and its principal metabolites in the serum of a patient receiving cimetidine for the treatment of Zollinger-Ellison syndrome, and have assessed use of the assay in a clinical setting.

The partitioning of cimetidine into canine cerebrospinal fluid.

The pharmacokinetics and cerebrospinal fluid (CSF) partitioning of cimetidine were studied in the dog. Four healthy male mongrel dogs were given a 22 mg/kg iv dose of cimetidine. The dogs demonstrated metabolic and pharmacokinetic characteristics similar to human volunteers, as the total body clearance of cimetidine averaged 7.5 ml/min/kg in the dog as compared to 7.7 ml/min/kg in humans. Autopsy tissue concentrations were similar to those measured in humans. There were no statistical differences between dogs and humans in any pharmacokinetic parameters. Cimetidine sulfoxide was the major metabolite in the dog, similar to that in humans. Cimetidine CSF partitioning, as determined by the ratio of cimetidine CSF:serum area under the curve was 0.125 +/- 0.03. Cimetidine appears to enter the CSF by passive diffusion, and is removed by passive diffusion, CSF bulk flow, and possibly by an active transport process. We conclude that the dog is an appropriate animal to investigate cimetidine pharmacokinetics and is a suitable model for examining the CSF uptake of H2-antagonists.