Clarence T. Ueda

Quinidine kinetics in congestive heart failure

The pharmacokinetics of quinidine was studied in cardiac patients with and without congestive heart failure. Following intravenous drug infusion, plasma and urine samples were collected at various times and analyzed for quinidine by a specific assay procedure. Although plasma quinidine concentrations varied over a wide range in both patient groups, the mean drug concentration at each time point was always higher in the congestive failure patients. In the 24‐hr postinfusion period, plasma drug disposition was biexponential with half‐life values for the fast and slow disposition processes (t½α and t½β) similar for each group. The respective values of t½α and t½β were 5.6 min and 6.8 hr in the congestive heart failure patients and 6.1 min and 6.2 hr in the control group. The volume of the central pool (Vc) and Vdarea were smaller in the congestive heart failure group (p < 0.05) with values of 0.44 ± 0.12 and 1.81 ± 0.49 L/kg, respectively, compared with those of the control group of 0.75 ± 0.31 and 2.67 ± 1.17 L/kg. Total body plasma drug clearance (Cl) was also lower in the heart failure patients (p < 0.05). The estimated Cl values were 3.16 ± 1.10 and 4.95 ± 1.36 ml/min/kg for the heart failure and control patients, respectively. Renal quinidine excretion accounted for 15% and 18% of the administered doses and corresponded to renal clearance values of 0.48 ± 0.15 and 0.95 ± 0.56 ml/min/kg in congestive heart failure and control patients, respectively. The results of this study indicate that the higher quinidine concentrations observed in congestive heart failure patients are due to a significantly smaller distribution volume for the drug.

Amiodarone pharmacokinetics. I. Acute dose-dependent disposition studies in rats

Single intravenous bolus doses of amiodarone hydrochloride of 30, 60, 90 and 120 mg/kg were administered to male Sprague-Dawley rats to determine the effects of dose on amiodarone pharmacokinetics. Serial blood samples and total urine were collected over 48 hr and assayed for amiodarone and desethylamiodarone by HPLC. The blood amiodarone concentration-time curves for the four doses were best described by a triexponential equation with terminal half-lives (t1/2γ) ranging from 17 to 20 hr. Over the dose range studied, no changes in γ, t1/2γ, or central compartment volume (Vc=1.2–1.4 L/kg) were observed. On the other hand, reductions in amiodarone clearance (CL and steady-state volume of distribution (Vss of 44% (17.7 to 10.0 ml/min per kg) and 50% (16.4 to 8.2 L/kg), respectively, were noted as the dose of amiodarone increased. The conversion of amiodarone to desethylamiodarone (fm was dose-independent and amounted to approximately 10% of each amiodarone dose. No amiodarone or desethylamiodarone was detected in the urine of any of the treated animals. The blood-to-plasma concentration ratio of amiodarone was concentration-independent and therefore did not account for the dose-dependent changes in Vssand CL observed. The data suggested that the dose-dependent changes noted were due to an alteration in the volume (s) of the peripheral tissue compartment(s).

Effects of Low and High Density Lipoproteins on Renal Cyclosporine A and Cyclosporine G Disposition in the Isolated Perfused Rat Kidney

AbstractPurpose. This study investigated the effects of low (LDL) and high density lipoproteins (HDL) on renal cyclosporine A (CsA) and cyclosporine G (CsG) disposition in the isolated perfused rat kidney model. Methods. Kidneys were perfused with CsA or CsG in perfusion medium containing 6% protein, bovine serum albumin only (BSA) (Control), LDL (200 mg/dl) and BSA, or HDL (200 mg/dl) and BSA. In vitro protein binding studies were conducted with CsA and CsG in the same media. Results. The unbound fractions (fu) of CsA and CsG were significantly reduced with LDL and HDL in the perfusion media. In the presence of LDL, fu for CsA and CsG was 3.9% and 5.9%, respectively. With HDL, fu was 2.1% for CsA and 1.8% for CsG. fu for the controls was 14.7% for CsA and 11.9% for CsG. Renal clearance (CLR) of CsA and CsG was significantly reduced when perfused with perfusion medium containing LDL and HDL. LDL and HDL had similar effects on reducing CsA and CsG CLR, and were ∼four-fold lower when compared to controls (∼0.006 Vs. 0.023 ml/min). Renal CsA and CsG tissue (whole organ, cortex and medulla) concentrations were lower than corresponding controls when perfused with LDL or HDL. Conclusions. The interaction of CsA and CsG with LDL and HDL significantly reduced the CLR and extent of renal tissue distribution of both compounds.

Serum disopyramide concentrations and suppression of ventricular premature contractions

Serum disopyramide determinations and 24‐hour Holter monitoring were performed in 20 cardiac subjects with ventricular premature contractions (VPCs) after the first, seventeenth, and thirty‐seventh doses of disopyramide, 100 mg (10 subjects; low‐dose group) or 200 mg (10 subjects; high‐dose group) every 6 hr for 10 days to assess the ability of single‐ or first‐dose data to predict serum disopyramide concentrations at steady state and the relationship between steady‐state serum disopyramide concentrations and VPC suppression. Control Holter recordings were made for 48 hr in each subject. There were strong correlations in both groups between data for the AUC over 0 to 6 hr for the first dose (AUC60) and average (C̄ss) and trough (Cmin) steady‐rate serum disopyramide concentrations after the seventeenth and thirty‐seventh doses and the two combined. C̄ss and Cmin were related to AUC60 by the following expressions for both dosage groups: C̄ss = 0.22 AUC60 + 0.90 and Ĉmin = 0.20 AUC60 + 0.70. There were good correlations between 6‐hr serum disopyramide concentration after the first dose and C̄ss and Cmin. There was strong correlation between overall average steady‐state serum disopyramide concentration and suppression of VPC frequency. The relationship between VPC suppression and overall average trough serum disopyramide concentration at steady state, on the other hand, was weak.

Effect of Column Temperature and Eluent Flow Rate on the High Performance Liquid Chromatographic Analysis of Cyclosporin A and D

On a reversed-phase C18 analytical column using an eluent of 70:30 acetonitrile and water, the following effects were observed with increasing column temperature (from 25 to 75°C) for Cyclosporin A (CSA) and Cyclosporin D (CSD). The peak heights and number of theoretical plates (N) increased. The height equivalent to a theoretical plate (HETP) decreased. The areas under the peaks, retention times and capacity factors (k′) for both compounds did not vary with temperature. With increasing eluent flow rate (from 0.5 to 2.5ml/ min), the peak heights, peak areas, retention times and N all decreased for both compounds. A slight decrease in k′ for CSA and CSD was also observed. HETP increased with increasing flow. The separation factor, α, remained relatively constant for the ranges of temperatures and flow rates investigated.

Effects of dihydroquinidine on in vitro and in vivo quinidine disposition.

The effects of dihydroquinidine on the metabolism of quinidine by 10,000 g supernatant fractions of rabbit and rat liver homogenates and on the disposition of quinidine in the rabbit were investigated. From Lineweaver-Burk plots, the following mean +/- S.E.M. values for V(max) and K(m) for quinidine and K(i) for dihydroquinidine for the rabbit liver preparations were obtained: 240 +/- 50 nmoles/min/g liver,0.55 +/- 0.14 mM, and 0.56 +/- 0.09 mM respectively. The corresponding values for the rat liver homogenates were 74 +/- 6 nmoles/min/g liver, 0.12 +/- 0.02 mM and 0.14 +/- 0.06 mM. From Dixon plots, the following values for K(i) for dihydroquinidine were obtained:0.54 +/- 0.09 mM for the rabbit liver preparations and 0.14 +/- 0.04 mM for the rat liver homogenates. In rabbits pretreated with dihydroquinidine for an average of 26 days, no changes in the distribution and elimination half-life values for quinidine, total body clearance, or apparent volume of drug distribution were observed when compared to the control quinidine disposition constants obtained in the same animals. As their structures suggested, the data showed that the interactions of dihydroquinidine and quinidine during drug metabolism by rabbit and rat liver 10,000 g supernatant fractions were competitive. Additionally, the affinities of dihydroquinidine and quinidine for the drug-metabolizing enzymes in these preparations were the same. The data also suggested that the small amounts of dihydroquinidine normally found in quinidine preparations probably have no significant effect on the disposition of quinidine in the body when therapeutic doses of the drug are used.

In Vitro Product Quality Tests and Product Performance Tests for Topical and Transdermal Drug Products

Two categories of tests are performed: (i) product quality tests and (ii) product performance tests. Product quality tests are intended to assess attributes of the dosage form whereas product performance tests are designed to assess the performance of the dosage form that in many cases is related to the drug release from the dosage form. Quality and performance tests together assure identity, strength, quality, purity, and performance of the drug product. All quality and performance tests for topical dosage forms are described.

Radiolabeled 9- or 10-monoiodostearic acid and 9- or 10-monoiodostearyl carnitine—I. Synthesis and purification

The purpose of this investigation was to synthesize and purify radiolabeled 9- or 10-monoiodostearyl carnitine for potential use as a perfusion and metabolic imaging agent for the heart. Oleic acid was iodinated via a free radical addition reaction of HI across the double bond to give 9- or 10-monoiodostearic acid which in turn was esterified with carnitine. The identity of 9- or 10-monoiodostearic acid and 9- or 10-monoiodostearyl carnitine was determined using nuclear magnetic resonance (NMR), infrared (i.r.), ultraviolet (u.v.), and mass spectroscopy. The purity of the fatty acid and carnitine ester was established by thin layer chromatography. 9- or 10-Monoiodo[125I]stearic acid and 9- or 10-monoiodo[125I]stearyl carnitine were synthesized via the isotopic exchange of 125I for cold iodine bonded to 9- or 10-monoiodostearic acid and 9- or 10-monoiodostearyl carnitine.