Pharmacokinetics, safety, and antiviral effects of hypericin, a derivative of St. John's wort plant, in patients with chronic hepatitis C virus infection.

Hypericin is a natural derivative of the common St. Johns wort plant, Hypericum perforatum. It has in vitro activity against several viruses, including bovine diarrhea virus, a pestivirus with structural similarities to hepatitis C virus (HCV). We conducted a phase I dose escalation study to determine the safety and antiviral activity of hypericin in patients with chronic HCV infection. The first 12 patients received an 8-week course of 0.05 mg of hypericin per kg of body weight orally once a day; 7 patients received an 8-week course of 0.10 mg/kg orally once a day. At the end of the 8-week period of treatment, no subject had a change of plasma HCV RNA level of more than 1.0 log(10). Five of 12 subjects receiving the 0.05-mg/kg/day dosing schedule and 6 of 7 subjects receiving the 0.10-mg/kg/day dosing schedule developed phototoxic reactions. No other serious adverse events associated with hypericin use occurred. The pharmacokinetic data revealed a long elimination half-life (mean values of 36.1 and 33.8 h, respectively, for the doses of 0.05 and 0.1 mg/kg) and mean area under the curve determinations of 1.5 and 3.1 microg/ml x hr, respectively. In sum, hypericin given orally in doses of 0.05 and 0.10 mg/kg/d caused considerable phototoxicity and had no detectable anti-HCV activity in patients with chronic HCV infection.

Multiple-dose pharmacokinetics and bioequivalence of L-carnitine 330-mg tablet versus 1-g chewable tablet versus enteral solution in healthy adult male volunteers.

The bioavailability and bioequivalence of three oral dosage forms of L-carnitine were studied in 15 healthy volunteers. Recently, an intravenous (iv) dosage form of L-carnitine has been approved to be marketed in the United States. The purpose of this study was to determine after multiple dose administration of the three oral dosage forms (marketed solution, chewable tablet, and marketed tablet) the pharmacokinetics and absolute bioavailability of each of the dosage forms at steady state and compare them with those following administration of a single iv dose. The relative bioavailability and bioequivalence of the chewable and marketed tablet relative to the marketed solution at steady-state replicate design conditions were also studied. Bioavailability based on data that was not corrected for the baseline (uncorrected data) was compared with bioavailability determined from data corrected for baseline. Steady-state conditions, based on free or total L-carnitine plasma concentrations, were achieved by Day 3, and products were bioequivalent based on the analysis of variance and comparisons by the two one-sided t test. Pharmacokinetic evaluations were found to be powerful tools for bioequivalence determinations; the power to detect 20% differences in AUC, Cmax tmax, and Cmin0 was > 80%. Mean absolute bioavailabilities (based on free or total L-carnitine plasma concentrations) on Day 4 (fraction of the dose absorbed) of Carnitor (levocarnitine) tablet, Carnitor (levocarnitine) oral solution, and levocarnitine chewable tablet relative to the first iv dose were approximately 18%. Similarly, absolute bioavailability compared with the last iv dose was approximately 18% for all three oral formulations.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of L-carnitine pharmacokinetics with and without baseline correction following administration of single 20-mg/kg intravenous dose.

L-Carnitine, a naturally occurring compound, is indicated in the treatment of primary systemic carnitine deficiency. To assess the differences in pharmacokinetic parameters calculated from data corrected for baseline versus those from "uncorrected" data, compartmental fitting was carried out for baseline corrected and original plasma concentration data obtained following a single intravenous (iv) dose of 20 mg/kg. For free L-carnitine, mean volumes of distribution at steady state (Vdss) of the central compartment were similar using either approach (9.86 versus 11.2 L). However, Vdss (54.0 versus 29.0 L) and apparent elimination half-life (17.4 versus 5.0 h) were significantly different between the two data bases. Similar observations were noted for pharmacokinetic parameters based on plasma concentrations of total L-carnitine. Although the pharmacokinetic parameters obtained after baseline correction may represent the kinetics of a bolus dose, the pharmacokinetic parameters from uncorrected plasma data probably represent the clinical settings for patients. Baseline correction also probably has its greatest value in attempting to determine and/or define the biological half-life and Vdss for the "exogenously" administered dose and uncorrected data best describes the pharmacokinetics of composite endogenous and exogenous L-carnitine levels.

Phenotypic differences in dextromethorphan metabolism.

Polymorphic differences in dextromethorphan metabolism were observed in three studies conducted in a total of 44 subjects (of Dutch origin) administered 60 mg dextromethorphan hydrobromide as an OROS tablet. Mean plasma dextromethorphan (DM) concentrations after a single dose and at steady state were 4-75 times higher in the poor metabolizers (PM) relative to the extensive metabolizers (EM). Following a single dose, the mean areas under the plasma concentration-time curve (AUC, 0-24 hr) of DM, total dextrorphan (DR), and total 3-hydroxymorphinan (HM) were 6.9-fold higher, 17.4-fold lower, and 11-fold lower, respectively, for the PM than for the EM. Correspondingly, steady-state AUC values were 52.8 times higher, 6.7 times lower, and 3.3 times lower for DM, total DR, and total HM, respectively, for the PM relative to the EM. Drug/metabolite ratios (DMR) for amounts excreted in the urine of DR and HM indicated polymorphism in O-demethylation of DM since DMR for PM was 352 and 338 times higher than that for EM for DR and HM, respectively. However, polymorphism in N-demethylation was not observed. Ratios of conjugated/free dextrorphan and 3-hydroxymorphinan excreted in the urine suggest also a lack of conjugative capacity in the PM, relative to the EM. The overall incidence of PM was 9.1% in this population.

Preliminary observations on dissolution and bioavailability of triamterene-hydrochlorothiazide combination products.

The dissolution profiles of two brands of triamterene-hydrochlorothiazide (TRM-HCT) combination tablets and two brands of TRM-HCT combination capsules were studied using the USP paddle method at 100 rev min-1 in acid medium (0.1N). The tablets represent two products marketed in Germany, whereas the capsules represent the approved innovator's product and an unapproved generic product. The tablets dissolved almost 100 per cent in 15 min whereas the capsules dissolved less than 25 per cent in 60 min. A pilot bioavailability study was carried out in four normal healthy male volunteers. Urine samples were collected over a 48 h period and analysed for TRM, its major metabolite TRM-sulfate, and HCT using HPLC methods. The dissolution characteristics of TRM can be associated with the total drug excretion (absorption) of the product. On the other hand, the excretion (absorption) of HCT was independent of dissolution characteristics of the products. However, in TRM-HCT combination product, there appears to be a 50 per cent reduction in HCT excretion (absorption) when compared to the reported excretion (absorption) from a marketed single-entity product.

Thiazides XI: partitioning of chlorothiazide in red blood cells after oral administration.

Uptake of chlorothiazide by red blood cells after oral drug administration was investigated. Chlorothiazide was administered to normal healthy volunteers as a solution or a tablet. Frequent blood samples were collected and analysed by a specific HPLC method. The results indicate that there is a significant uptake of chlorothiazide by red blood cells, resulting in a higher blood AUC compared to plasma AUC.

Bioavailability of propylthiouracil in humans.

Single lots of five commercially available 50-mg propyl-thiouracil formulations were evaluated in vitro and in vivo. Each product met the USP XIX specifications for drug content, content uniformity, and disintegration time. However, major differences were noted among products in their rate and extent of dissolution. Statistically significant differences (p less than 0.05) were observed in vivo among the drug formulations at all but one of the sampling times, as determined from crossover blood level studies in 12 healthy male volunteers. The differences among the areas under the plasma level-time curves for the various products were not statistically significant. No statistically significant correlations were found between the in vitro and in vivo parameters studied.

Phenytoin I: in vitro-in vivo correlation for 100-mg phenytoin sodium capsules.

Dissolution profiles for 11 brands of phenytoin sodium capsules were carried out by the basket and paddle methods (USP) and the spin-filter method. The results from the dissolution studies have been correlated with observed differences in in vivo parameters (Cmax and tmax). The dissolution by the basket method at 50 rpm in water gave a correlation greater than 0.9. The results suggest the existence of two types of phenytoin sodium products on the market.

Phenytoin II: in vitro-in vivo bioequivalence standard for 100-mg phenytoin sodium capsules.

A bioequivalence study was undertaken using an oral solution, a fast-dissolving capsule and a slow-dissolving phenytoin sodium capsule. The AUC, tmax and Cmax correlated with in vitro dissolution data. The results of the present studies substantiate the presence of two types of phenytoin sodium products on the market. On the basis of these studies, in vitro specifications for fast- and slow-dissolving phenytoin sodium capsules as well as the in vivo bioequivalence requirements for these two types of products are recommended.

Evaluation of basket and paddle dissolution methods using different performance standards.

Dissolution studies using both basket and paddle methods were carried out to evaluate two prednisone standards. Results of the experiments showed that the USP prednisone calibrator is sensitive to perturbations by the basket method but not to perturbations by the paddle method. However, the National Center for Drug Analysis (NCDA) prednisone performance standard is sensitive to perturbations by the paddle method but not to perturbations by the basket method. These results suggest that no single standard can predict the suitability of the dissolution equipment by the basket and paddle methods.

Thiazides III. Evidence of dose proportionality of hydrochlorothiazide 25, 50 and 100 mg tablets.

A pilot bioavailability study was carried out where two subjects each were administered a dose of 25, 50 or 100 mg of commercially available hydrochlorothiazide (HCT) tablets. Plasma and urine samples were collected and analyzed by HPLC. A maximum plasma concentration of 50-285 ng/ml was reached in 1-2 hours, and plasma levels declined very rapidly with a half life of about 2-4 hours during first 12 hours period. The AUC was calculated using the trapezodial rule. A linear correlation was seen between the dose administered and amount of drug excreted.

Thiazides IV: Comparison of dissolution with bioavailability of chlorothiazide tablets.

Based on the initial dissolution rate profiles in water, a slow-dissolving, an intermediate-dissolving, and a fast-dissolving chlorothiazide 250-mg tablet were selected for the bioavailability and bioequivalence study. In addition, two marketed 500-mg chlorothiazide tablets were studied. The three 250-mg tablets were bioequivalent, as were the two 500-mg tablets. Therefore, the dissolution test conditions were modified to associate in vitro dissolution with in vivo performance of the product. Based on these results, it was concluded that a dissolution of 75% in 60 min by paddle method at 75 rpm in pH 7.4 phosphate buffer can be used as a quality assurance test for 250- and 500-mg chlorothiazide tablets.

Improved method for the analysis of furosemide in plasma by high-performance liquid chromatography.

Modifications of existing rapid high-performance liquid chromatographic procedures for the determination of furosemide in plasma were made in order to achieve greater sensitivity. To a small volume of plasma was added in internal standard structurally related to furosemide. Then, following previously described procedures, acetonitrile was added to precipitate the proteins and the clear supernatant was separated. However prior to injection of the supernatant the pH and composition of the sample were adjusted. This modification of the sample enabled an injection volume of up to 300 microliters of the supernatant to be injected onto the chromatographic column. The effluent was monitored spectrofluorimetrically. A standard linear calibration curve with a mean precision of +/- 4.4% was obtained for plasma samples containing 20--900 ng/ml of furosemide. Two structurally related compounds were used as internal standards in the furosemide assay.

Dissolution profiles and specifications for dihydroergotoxine sublingual tablets using a new in vitro method.

A dissolution method (paddle method) for determining the dissolution rate profile for 0.5- and 1.0-mg dihydroergotoxine methanesulfonate sublingual tablets was developed. A fluorometric method was used for measuring drug concentration in the dissolution medium, distilled water. It was essential to filter the dissolution sample to avoid interference from undissolved excipients. When different kinds of filters were used with the dissolution samples and standards, different degrees of apparent drug binding to the filter occurred. The dissolution rate profiles for several different products were compared to the innovator's product. The in vitro method and data obtained were used to propose dissolution specifications for these sublingual products.