The pharmacokinetics and pharmaco-dynamics of Procysteine in amyotrophic lateral sclerosis.

In 13 subjects with ALS, we studied the safety and pharmacokinetic properties of Procysteine, a cysteine prodrug that increases levels of intracellular glutathione. We found that oral administration of Procysteine was safe. Procysteine enters CSF after both IV and oral dosing and accumulates to significant levels in CSF. We also observed that CSF levels of glutathione fall dramatically with aging.

Pharmacokinetics of 2-oxothiazolidine-4-carboxylate, a cysteine prodrug, and cysteine.

The pharmacokinetics of both 2-oxothiazolidine-4-carboxylate (OTZ), a prodrug of cysteine, and total blood cysteine (cysteine plus cystine) were investigated in 18 healthy volunteers. OTZ was given either as a single, 2-hour intravenous infusion (56-66 mg/kg) or similarly infused (70-100 mg/kg) every 8 hours for four doses. Blood was assayed for OTZ, total blood cysteine, and glutathione. The pharmacokinetics of OTZ were analyzed alone and simultaneously with total cysteine using the NONMEM software package (University of California at San Francisco. The pharmacokinetics of OTZ were best described by Michaelis-Menten kinetics with parallel first-order elimination. OTZ was efficiently removed from the plasma. The Michaelis-Menten route of elimination was attributed to conversion of OTZ to total cysteine. At plasma OTZ concentrations equal to the Michaelis constant Km, 84% of OTZ was converted to total cysteine. These findings suggest that OTZ administered intravenously is an efficient means of increasing total blood cysteine.

Colorimetric determination of hydroxyurea in human serum using high-performance liquid chromatography.

A high-performance liquid chromatography assay for hydroxyurea in human serum was developed based on a commercial colorimetric assay kit for urea (Sigma Diagnostics). Serum (0.5 ml), spiked with methylurea as an internal standard, was treated with 70% perchloric acid. Supernatant (0.2 ml) was combined with 0.7 ml of BUN acid reagent and 0.6 ml of BUN color reagent. The resulting colored reactant (100 microl) was analyzed on a 300 x 3.9 mm Bondclone 10 C18 column coupled with a UV-Vis detector, at 449 nm. The mobile phase was 13% acetonitrile in water. Retention times of colored derivatives of hydroxyurea and methylurea were 6.5 and 12.2 min, respectively. The log-log calibration curve was linear from 0.0065 to 1.31 mM. Average accuracy was 99.9+/-4.0% and the intra- and inter-day error of assay did not exceed 11%.

Assay for etoposide in human serum using solid-phase extraction and high-performance liquid chromatography with fluorescence detection.

An HPLC assay for etoposide in human serum was developed. Serum, spiked with podophyllotoxin (internal standard), was treated with sodium dodecyl sulphate prior to solid phase extraction. Analysis was performed on a 300x3.9 mm Bondclone 10 C18 column coupled with a fluorometric detector (lambda(ex) 230 nm, lambda(em) 330 nm). The retention times for etoposide and podophyllotoxin were 14 and 28 min respectively. The range of assay was 0.5 to 20 microg/ml with a detection limit of 0.2 microg/ml. This assay is suitable for use in clinical studies with etoposide.

Pharmacokinetics and pharmacodynamics of hydroxyurea.

Hydroxyurea is used in the treatment of various forms of cancer, sickle-cell anaemia and HIV infection. Oral absorption of the drug is virtually complete, the volume of distribution is equivalent to total body water and elimination is through both renal and nonrenal mechanisms. Nonrenal elimination of hydroxyurea is characterised by Michaelis-Menten kinetics. Further studies are necessary to clarify several aspects of the pharmacokinetics and pharmacodynamics of hydroxyurea: the effect of age and disease state, concentration-effect relationship, the role of therapeutic drug monitoring, and the mechanisms of renal and nonrenal elimination. The recent development of improved assays for hydroxyurea should have benefits for future pharmacokinetic studies.

Population pharmacokinetics of glyburide in patients with well-controlled diabetes.

STUDY OBJECTIVES: To investigate glyburide pharmacokinetics in patients with well-controlled noninsulin-dependent diabetes mellitus (NIDDM), and test the hypothesis that intersubject variability in the glyburide dose is due to patient differences in the drug's pharmacokinetics. METHODS: Prospective, open-label study. SETTING: University-affiliated, internal medicine outpatient clinic. PATIENTS: Fifty-one patients with NIDDM (11 women, 40 men, mean age 56.7 +/- 15.3 yrs) receiving oral glyburide and with well-controlled glycohemoglobin levels 10.0% or below. INTERVENTION: After fasting overnight, patients ingested their regular morning dose of glyburide and then ate breakfast. Blood samples were drawn before dosing and between 0.5-2 hours, 2-5 hours, and 5-10 hours after dosing. MEASUREMENTS AND MAIN RESULTS: Serum glyburide was assayed by high-performance liquid chromatography and pharmacokinetics by NONMEM. Glyburide clearance was proportional to weight and greater in older patients (> 60 yrs). CONCLUSION: Variability in the glyburide dose was not primarily due to intersubject differences in the drug's pharmacokinetics.

Population pharmacokinetics of hydroxyurea in cancer patients.

The pharmacokinetics of hydroxyurea (HU) were investigated in cancer patients after intravenous infusion or oral administration. On the basis of the minimal value of the objective function (MVOF) and prior knowledge of the disposition of HU in animals and man, the data were best described by a one-compartment pharmacokinetic model with parallel Michaelis-Menten metabolism and first-order renal excretion. The computer program NONMEM (nonlinear mixed effects model) was used to perform the nonlinear regression and provide estimates of the population parameters. For the combined intravenous and oral data set, these parameters were estimated to be: maximal elimination rate (Vmax), 0.097 mmol h-1 l-1; Michaelis constant for HU elimination (KM), 0.323 mmol/l; renal clearance (ClR), 90.8 ml/min; volume of distribution (Vd), 0.186 x (body weight) + 25.4 l; absorption rate constant (Ka), 2.92 h-1; and availability to the systemic circulation (F), 0.792. The principal findings of the investigation are that HU undergoes nonlinear elimination in cancer patients and that HU is reasonably well absorbed following oral administration.

The effect of garlic extract on human metabolism of acetaminophen.

Several studies suggest that the constituents of garlic may inhibit experimentally induced carcinogenesis. To evaluate the chemopreventive properties of garlic in humans, the effects of chronic administration of an aged garlic extract on the disposition of acetaminophen and metabolites were studied. This commonly used drug was chosen because it forms a reactive electrophilic metabolite after oxidative metabolism. Sixteen subjects ingested daily doses of garlic extract (approximately equivalent to six to seven cloves of garlic) for 3 months. Before the course of garlic, at the end of each month and 1 month after termination of garlic administration, a 1-g oral dose of acetaminophen was given to each subject. Plasma and urine were measured for acetaminophen and the glucuronide, sulfate, cysteinyl, mercapturate, and methylthio metabolites. It was found that garlic treatment had no discernible effect on oxidative metabolism but was associated with a slight increase in sulfate conjugation of drug. These findings suggest that garlic extract has limited potential as a chemopreventive agent.

Clofibrate enhances the DNA damaging action and cytotoxicity of nitrosoureas.

The ability of N-ethyl-N-nitrosourea (ENU) to produce single strand breaks (SSB) and N,N'-bis(2-chloroethyl)-N-nitrosourea (BCNU) to produce SSB and DNA-DNA interstrand cross-links was measured in L1210 cells that had been pretreated with clofibrate (CLO). When ENU was used the SSB frequency rose from 12.4 +/- 1.6/10(6) bases in control cells to 17.3 +/- 1.5/10(6) bases in CLO-treated cells and from 2.8 +/- 0.1/10(6) bases in control cells to 5.5 +/- 0.4/10(6) in CLO-treated cells when BCNU was the damaging agent. Similarly the cross-linking frequency rose from 3.5 +/- 0.1/10(6) bases in control cells to 12.1 +/- 0.5/10(6) bases in CLO-treated cells when BCNU was the cross-linking agent. CLO treatment increased the production of superoxide anion four-fold over the controls and it increased the cytotoxicity of BCNU. Forty-two percent of the control+BCNU cells survived after 24 h whereas only 24% of the CLO+BCNU cells survived. The stimulation of the diffuse condition known as oxidative stress increased the interaction of nitrosoureas with DNA and resulted in increased biological responses, e.g. cytotoxicity.

A phase I trial of high-dose continuous-infusion hydroxyurea.

Hydroxyurea inhibits ribonucleotide reductase, resulting in depletion of intracellular deoxynucleotide pools and inhibition of DNA repair. It has been used in a variety of malignancies and is usually given orally. Deoxynucleotide depletion is directly related to the concentration of and duration of exposure to hydroxyurea; thus, prolonged continuous infusion may result in increased therapeutic efficacy. A total of 30 patients were treated on this trial, designed to determine the maximum tolerated doses (MTD) of intravenous hydroxyurea given as a 24- or 48-h continuous infusion. The MTD for the 24-h infusion was 13,520 mg/m2 following a bolus of 1,690 mg/m2, and the mean (+/- SD) plasma steady-state concentration was 1.93 +/- 0.52 mM. For the 48-h infusion, the MTD was 17,576 mg/m2 following a bolus of 2,197 mg/m2 and the mean steady-state level was 1.43 +/- 0.31 mM. The dose-limiting toxicity on both schedules was marrow suppression manifesting as neutropenia and thrombocytopenia. Pharmacokinetic analysis revealed decreasing clearance with increasing dose, implying that drug elimination is saturable. Pharmacodynamic analysis showed a slight correlation between steady-state plasma levels and the degree of marrow suppression.

The effects of diabetes mellitus on pharmacokinetics and pharmacodynamics in humans.

The article reviews the effect of diabetes on the pharmacokinetics and pharmacodynamics of drugs in humans. For most drugs which cross the gastrointestinal wall by passive diffusion, oral absorption is unlikely to be affected by diabetes, although a delay in the absorption of tolazamide and a decrease in the extent of absorption of ampicillin have been reported. Subcutaneous absorption of insulin is more rapid in diabetic patients, whereas the intramuscular absorption of several drugs is slower. The binding of a number of drugs in the blood is reduced in diabetes, which may be due to glycosylation of plasma proteins or displacement by plasma free fatty acids, the level of which is increased in diabetic patients. Plasma concentrations of albumin and alpha 1-acid glycoprotein do not appear to be changed by the disease. The distribution of drugs with little or no binding in the blood is generally not altered, although the volume of distribution of phenazone (antipyrine) is reduced by 20% in insulin-dependent diabetes mellitus (IDDM). In contrast to animal studies, the metabolic clearance of most drugs in humans appears to be unaffected or slightly reduced by the disease. The presence of fatty liver in non-insulin-dependent diabetes mellitus (NIDDM) may contribute to a reduced hepatic clearance, whereas decreased binding in the blood may cause an increase in clearance. The effect of diabetes on hepatic blood flow in humans appears to be unknown. Diabetes affects kidney function in a significant number of diabetic patients. During the first 10 years after the onset of the disease, glomerular filtration is elevated in these patients. Thus, the renal clearance of a number of antibiotics has been shown to be increased in diabetic children. As the disease progresses, renal function is impaired and glomerular function declines from the initial elevated state. In diabetic adults the renal clearance of drugs either is comparable with that found in nondiabetic individuals or is reduced. A limited number of studies have been conducted comparing the dose-response of cardiovascular drugs in diabetic patients with that in nondiabetic controls. Decreased, increased and unchanged responses have been reported. It is apparent that in some cases an altered response may be observed for a drug when administered to a diabetic patient compared with a similar nondiabetic individual. At the present time, it is not possible to ascertain whether these studies reflect true pharmacodynamic changes or merely alterations in pharmacokinetics.(ABSTRACT TRUNCATED AT 400 WORDS)

Pharmacokinetics of disopyramide in the dog. Importance of mono-N-dealkylated metabolite kinetics in assessing pharmacokinetic modeling of the parent drug.

The antiarrhythmic drug disopyramide (DP) is metabolized to the mono-N-dealkylated compound (MND) and to the pyrrolidone derivative (PYR). This study examines the detailed pharmacokinetic characteristics of DP and MND when given simultaneously or separately to dogs. DP and MND were both relatively well absorbed and showed similar pharmacokinetic characteristics. However, the amount of PYR relative to MND as judged by the area under the plasma concentration-time curves (AUC) following oral or iv administration was much greater with DP than with MND. These findings were also supported by the urinary excretion values where the PYR/MND ratio with DP was much greater than with the MND administration. For an explanation of this phenomenon, plasma concentration-time curves for DP, MND, and PYR were simultaneously analyzed assuming various pharmacokinetic models. The plasma levels of these compounds were best described when nonlinear kinetics were assumed for conversion of MND to PYR.

Time to steady state following a change in dosing rate.

Drugs administered at fixed intervals or by continuous infusion will accumulate in the body until steady state is achieved. The time to a given percentage of the eventual steady-state concentration has previously been considered to be dependent only on the elimination half-life. This is incorrect. Although the rate of drug accumulation in the body is dependent only on the elimination half-life, the time to a given percentage of steady state is dependent on both the elimination half-life of the drug and the initial concentration. This paper presents the mathematical proof of this concept, computer simulations demonstrating the use of these equations, and nomograms for use in clinical practice. The use of this method allows serum drug concentrations to be evaluated earlier than previously predicted after changes in the dosing rate.

Removal of sulfonamides by hemofiltration.

Hemofiltration is a relatively new technique for removing toxic substances from the body. Unlike hemodialysis or hemoperfusion, the driving force behind hemofiltration is ultrafiltration. There have been several studies examining the clearance of drugs by hemofiltration but to date no study has investigated in a systematic way the effects of protein binding, perfusate flow, transmembrane pressure, and the duration of treatment on drug clearance by hemofiltration. The influence of these factors on the hemofiltration clearance of three sulfonamides with differing degrees of protein binding was investigated. It was found that hemofiltration drug clearance decreased with the duration of hemofiltration and protein binding but increased with perfusate flow and transmembrane pressure.

The influence of diffusional barriers on presystemic gut elimination.

A number of drugs undergo biotransformation in the gut wall or lumen. In many cases drug extraction is greater after oral administration compared with parenteral administration. This may indicate that the diffusional clearance of drug across the blood-mucosa interface is less than that across the lumen-mucosa interface. The consequence of diffusional barriers in the gut on presystemic gut elimination (PGE) have been investigated by computer simulation of a physiological pharmacokinetic model. The following was found regarding a diffusional barrier of the blood-mucosa interface: 1) it enhances PGE, 2) it invalidates certain pharmacokinetic methods to assess PGE, 3) it makes PGE sensitive to changes in drug binding in the blood, and 4) if the diffusional barrier exists for the generated metabolite but not for the drug, methods to assess drug absorption by comparing area under the curve relationships of the metabolite after oral and iv drug administration are inaccurate.

Steady state absorption kinetics and pharmacodynamics of furosemide in congestive heart failure.

Furosemide, a potent loop diuretic, is commonly used in the treatment of congestive heart failure (CHF). Unpredictability in the diuretic effect following oral doses has been attributed to variable and incomplete absorption and to variability in the pharmacodynamic response to furosemide. The present study is undertaken to investigate the absorption kinetics and pharmacodynamics of furosemide in patients with CHF during chronic medication. Ten patients with congestive heart failure were maintained on 40 to 160 mg furosemide for a month. The final dose at the end of this period was administered on an empty stomach. Plasma and urine were collected and assayed for furosemide, potassium, chloride, sodium and creatinine. Urine flow was also measured as a function of time. Plasma furosemide concentration-time data were fit to a two-compartment model with either two consecutive, discontinuous first order absorption rate constants or with a single monoexponential input; the former absorption model describing the data better than the latter. Average values of the half-life (205 +/- 28 min) and renal clearance (0.8 +/- 0.09 ml/min/kg) were similar to those reported by previous investigators. Drug excretion-response curves were lower and shifted to the right compared to data reported for normal subjects. Furthermore, a clockwise hysteresis was evident indicating acute within-dose tolerance.

The effect of activated charcoal on mouse sleep times induced by intravenously administered hypnotics.

The effect of orally administered activated charcoal (AC) on the sleep times of mice following intravenous injection of various hypnotics was investigated. Preliminary studies with phenobarbital (Pb) showed that a linear relationship exists between the Pb-induced sleep time and the logarithm of the Pb dose in both control and AC treated mice. Half-lives of Pb in the two groups were estimated to be 8.1 and 0.9 h, respectively. A linear decline in Pb-induced sleep time with increasing dose of AC was observed up to a maximum effective dose of AC beyond which dose increments caused no further reduction in sleep time. A similar relationship was observed between sleep time and the concentration of sodium sulfate in which the AC was suspended. AC treatment resulted in an 82-88 per cent reduction in sleep time induced by administration of phenobarbital, methyprylon, glutethimide, ethchlorvynol, and methaqualone. AC had no significant effect on sleep time following amobarbital or pentobarbital administration.

Absorption and disposition of aluminum in the rat.

The kinetics of aluminum were determined in the rat. Intravenous bolus and oral doses of 8.1-mg/kg of aluminum as the chloride salt were administered to six rats. Serial blood samples and total urine and feces were collected and assayed for aluminum by atomic absorption spectrophotometry. The fraction absorbed orally (mean +/- SEM) was 0.27 +/- 0.03; the half-life was 5.29 +/- 0.47 h; the steady-state volume of distribution was 38.4 +/- 6.4 mL/kg, and the clearance was 8.87 +/- 1.76 mL X h-1 X kg-1. It was found that aluminum did not significantly penetrate the cellular components of blood. Plasma protein binding was determined to be approximately 98%. Sixty percent of the intravenous dose was excreted in the urine and the remaining 40% was excreted in the feces.