Disopyramide is a class IA antiarrhythmic agent which shares a number of pharmacological properties with quinidine and procainamide. Clinically, it is effective in the treatment of supraventricular tachycardia, atrial fibrillation, ventricular tachycardia and premature ventricular contractions. Disopyramide, a basic drug, has been shown in the past to be bound to acute phase reactant, alpha₁-acid glycoprotein (AAG) in a concentration-dependent manner. Disopyramide has been known to demonstrate a steep serum concentration-pharmacological effect relationship. The primary metabolic pathway of disopyramide in humans is N-dealkylation which is susceptible to enzyme induction,as indicated by a few preliminary studies. The pharmacological role of the mono-N-dealkylated metabolite (MND) of disopyramide in humans is not fully established. This thesis describes the development of an improved gas-liquid chromatographic (GLC) assay for the simultaneous quantitation of trace levels of disopyramide and MND in human biological fluids and the application of the method in in vitro plasma protein-binding of disopyramide. This thesis also describes and discusses the effect of phenobarbital treatment on the serum protein-binding and single dose pharmacokinetics of disopyramide in non-smokers and smokers. A GLC-nitrogen/phosphorus specific detection (NPD) assay has been developed which provides improved selectivity and sensitivity for disopyramide and MND, employing a fused-silica capillary column for chromatographic separation from biological specimen components. The quantitation of disopyramide and MND in human serum, saliva and urine was accomplished by injecting trifluoro-acetic anhydride (TFAA)-treated samples containing the internal standard, p-chlorodisopyramide (PC-Dis), into a gas chromatograph equipped with a nitrogen/phosphorus detector (NPD) and an automatic liquid sampler (ALS). A 25 m (i.d. = 0.31 mm) fused-silica column, coated with crosslinked 5 % phenyl methyl silicone fluid was utilized and samples were injected using the splitless sample injection mode. Linearity was observed in the serum concentration range from 0.05 to 5.0 mcg/ml for disopyramide and from 0.02 to 3.0 mcg/ml for MND. The average coefficient of variation was 5 and 8 % for disopyramide and MND, respectively, over the concentration range studied. The capillary GLC-NPD assay was utilized to measure disopyramide concentration, unbound to plasma protein, following equilibrium dialysis of plasma samples collected from healthy volunteers. Various concentrations of disopyramide ranging from 0.5 to 10 mcg/ml in 0.4 ml of isotonic phosphate buffer (pH 7.4) were dialysed for 6 hours at 37°C, against 0.4 ml blank plasma from five healthy volunteers. The concentration-dependent binding of disopyramide was verified. The average unbound fractions for disopyramide, at concentrations 0.5, 1, 2, 3, 4, 5 and 10 mcg/ml, were 0.14, 0.15, 0.20, 0.28, 0.30, 0.35 and 0.55, respectively. The effect of phenobarbital treatment on the pharmacokinetics and binding of disopyramide was studied in non-smoking volunteers: (1) Because of the potential pharmacological and toxicological significance of the major metabolite of disopyramide, (2) due to the need to develop a better understanding of the effect of phenobarbital treatment on the serum concentration of alpha₁-acid glycoprotein (AAG), the principal binding protein of disopyramide and other basic drugs and (3) to provide insight into the selectivity of phenobarbital induction as compared to literature data on other inducers (rifampin, phenytoin, carbamazepine and spironolactone). Eight healthy male subjects received a 200 mg oral dose of disopyramide on 2 occasions separated by a 3 week period during which phenobarbital was taken (100 mg p.o.) at bedtime yielding a mean steady-state concentration of 14 ± 2 mcg/ml. Serum, saliva and urine collections were obtained following each disopyramide dose. The serum concentration versus time data were analysed by AU TOAN and NONLIN computer programs and were found to fit a one-compartment open pharmacokinetic model. The apparent terminal phase elimination half-life (t½) of disopyramide was shorter (p < 0.05) in subjects during phenobarbital treatment (4.6 ± 0.7 hr) (mean ± S.D.) than during the control experiment (6.5 ± 1.5). Furthermore, an index of the amount of drug in the body, the area under the disopyramide serum concentration versus time curve (AUC), was markedly reduced from control (27 ± 6 hr.mcg/ml) after phenobarbital (17 ± 6 hr.mcg/ml, p < 0.05). The AUC₀₋₂₄ʰʳ for the principal metabolite of disopyramide (mono-N-dealkyl disopyramide or MND) increased (3.8 ± 1.6 hr.mcg/ml for control vs 4.1 ± 2.3 hr.mcg/ml in pheno-barbital-treated subjects) but this change was not statistically significant. Phenobarbital treatment caused no observable trend towards a change in disopyramide unbound fraction (0.23 ± 0.02 vs 0.21 ± 0.02) or in serum AAG concentration (50 ± 15 vs 54 ± 18 mg/100 ml), as has been observed in dogs in the past. The ratio of MND to disopyramide in saliva was consistently higher in phenobarbital-treated subjects. The average percentage of dose recovered in urine as unchanged disopyramide in 48 hrs was 43 ± 6 % and 25 ± 5 % (p < 0.05) in control and phenobarbital-treated subjects, respectively. The average percentage of dose recovered as MND in 48 hours was 25 ± 6 % in controls and 33 ± 7 % in phenobarbital-treated subjects. It can be concluded from our study that the enzyme inducer phenobarbital enhances disopyramide metabolism but does not alter the serum AAG levels or the binding of disopyramide to this protein in normal subjects. The effect of chronic cigarette smoking and the combined effect of smoking and phenobarbital treatment on the disopyramide pharmacokinetics and serum AAG levels were also investigated. The general procedures such as dosing and physiological monitoring of smokers, sampling protocols of smokers before and during phenobarbital-treatment, sample collection and analytical methods were identical to the non-smoking study. There was no difference in the pharmacokinetic parameters or serum AAG concentrations between the smoking and the non-smoking volunteers when studied and compared in the absence and presence of phenobarbital treatment. Therefore, it appears that the metabolic bio-transformation of disopyramide remains unaffected by chronic cigarette smoking. These findings support the general view that the induction of hepatic microsomal oxidation of a particular drug is highly selective in humans and is a function of substrate or drug specificity for a particular form of cytochrome P-450. / Pharmaceutical Sciences, Faculty of / Graduate

Metoclopramide (MCP) is a potent antinauseant/ antiemetic and gastrointestinal motility modifier. MCP finds clinical use in a wide variety of situations and is administered on both an acute and chronic basis. This thesis examines the pharmacokinetics of MCP in both normal, healthy volunteers and in uremic subjects on a maintenance hemodialysis program. Specifically, in the normal, healthy volunteers, the dose-linearity, and absolute and relative bioavailabilities are examined. In the uremics, the effects of chronic renal failure on MCP kinetics, the removal of MCP by hemodialysis, and the effects of hemodialysis on MCP kinetics are examined. Based on early reports, the pharmacokinetics of MCP were claimed to be dose-dependent and the absolute bioavailability extremely variable. However, many of these early studies suffered from methodological problems which limit the credibility of their findings. Based on a four-way crossover study involving six normal, healthy volunteers we find, in contrast to previous results, that the kinetics of MCP are linear over the dose range of 5 -20 mg, the absolute bioavailability is 76 ± 38 %, and the relative bioavailability of a solution dosage form vs the tablet dosage form is approximately 1. Although renal clearance accounts for only about 20 % of the total body clearance of MCP in normals, uremia has been shown to substantially alter MCP kinetics in both rat and man. There appears to be at least a two-fold decrease in total body clearance with an attendent, proportional increase in elimination half-life and insignificant change in volume of distribution. Hemodialysis is relatively ineffective in clearing MCP from the body and this inefficiency is probably related to the relatively large volume of distribution of MCP. Hemodialysis also has no effects on the apparent kinetic parameters following its termination. In addition, results from a single patient who received a kidney transplant show that the renewed renal function is accompanied by an apparent reversion of all kinetic parameters to within normal limits within 15 days of transplantation. / Pharmaceutical Sciences, Faculty of / Graduate

In view of the fact that some fat soluble vitamins are toxic in large doses to experimental animals and man, this study was initiated to investigate the long-term effects of low, moderate and high levels of dietary vitamin E on various metabolic parameters in the rat. Six groups of female Wistar rats (50 g) were fed for as long as 16 months the basal vitamin E-free diet with supplements ranging from 0 to 25»000 IU vitamin E (DL-a-tocopheryl acetate) per kilogram diet. The levels of vitamin E chosen were 0, 25, 250, 2,500, 10,000 and 25,000 IU/kg diet; 0 representing vitamin E-free, 25 representing moderate level and 250 to 25»000 representing large doses. All nutrients in the basal diet except vitamin E were adequate. The focus of this study was on the effects of large doses of dietary vitamin E on: (l) the hematological indices such as hematocrit and hemoglobin levels, prothrombin time and erythrocyte hemolysis at 9, 12 and 16 months of treatment; (2) urinary creatine and creatinine levels at 11 months of treatment; (3) body weight and various organ weights at 8 and 16 months of treatment; (4) femoral parameters such as ash content, and calcium and phosphate concentrations of bone at 8 and 16 months of treatment; and (5) the levels of a-tocopherol, vitamin A, total lipids, and cholesterol in liver and plasma at 8 and 16 months of treatment. Rats fed 10,000 and 25.000 IU vitamin E/kg diet for 8 and 16 months had significantly reduced body weights in comparison to those receiving the moderate level of vitamin E. The depressing effect of excess dietary vitamin E on body weight was not as marked as that of vitamin E deficiency. There was little difference between the moderate and high vitamin E supplemented groups with respect to the weights of liver, uterus and kidney. However, high levels of dietary vitamin E increased the relative heart weights after 8 months and the spleen weights after 16 months. Hemoglobin and hematocrit values were not influenced by excessive amounts of vitamin E after 9 or 12 months of treatment. At 16 months however, the hematocrit values of rats fed 10,000 and 25,000 IU vitamin E/kg diet were increased significantly over those of rats fed 25 IU/kg diet. The prothrombin time was reduced in rats treated with excess dietary vitamin E for 12 and 16 months. Only vitamin E deficiency, but not excess vitamin E, was associated with increased membrane fragility of erythrocytes. In rats subjected to excess vitamin E for 16 months the ash content of bone was decreased. High levels of dietary vitamin E increased the plasma alkaline phosphatase activity after 16 months of treatment. These results indicate that there may be increased mineral turnover in bones of rats fed high levels of vitamin E for prolonged periods. Urinary levels of creatine and creatinine were not affected by high levels of dietary vitamin E. However, in the vitamin E deficient rats, the creatine excretion increased while the creatinine excretion decreased, resulting in a very high ratio of creatine/creatinine in urine. The α-tocopherol stored in liver rose significantly with increasing dietary vitamin E. A logarithmic relation was demonstrated between liver α-tocopherol concentration and dietary levels of vitamin E. The total α-tocopherol in whole liver of rats fed the different levels of vitamin E for 16 months was approximately double that in rats treated for 8 months. A curvilinear relationship between plasma tocopherol and the logarithm of dietary vitamin E was found in rats treated for 8 and 16 months. Total lipids in liver increased significantly with increasing dietary vitamin E in rats treated for 8 months, but not in rats treated for 16 months. There was little difference in liver cholesterol concentration between the moderately supplemented and highly supplemented groups. Increasing dietary vitamin E significantly lowered plasma total lipids and cholesterol in rats treated for 16 months. A quantitative examination of the data showed that the reduction in plasma total lipids was not simply a reflection of the cholesterol levels, and suggests that a high dietary level of vitamin E affected one or more of the constituents of the total lipids (phospholipids and/or triglycerides) other than cholesterol. From the findings of this long-term study, it appears that high levels of dietary vitamin E result in biochemical changes in some aspects of metabolism in rats. Some of the changes worth recognition are the depression in body weight, increase in relative spleen and heart weights, decrease in ash content of bones with concurrent increase in plasma alkaline phosphatase activity, increased hematocrit value and fatty liver in rats treated for 8 months. A logarithmic relationship was observed between dietary levels of vitamin E and the concentrations of this vitamin in liver and plasma. The results of this study suggest that excess vitamin E over prolonged periods of time have some harmful effects in rats. / Land and Food Systems, Faculty of / Graduate

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A novel pyronaridine-artesunate (PA) combination is being developed as a 3:1 fixed ratio oral combination against P. falciparum and P. vivax malaria. Pyronaridine (PYR) has been used on a limited basis as monotherapy to treat malaria in some provinces in China since 1970, and there are minimal published data on pharmacokinetics of PYR in humans. In this thesis, the population pharmacokinetics (PPKs) of PYR is studied in different populations. In Chapter II, we develop a PPKs model in 91 healthy subjects participating in a Phase I study of PA. In addition, data from two Phase II and four Phase III studies of PA are pooled, and PPKs of PYR in 321 adult and 319 pediatric patients are investigated separately in Chapter III and IV, respectively. Chapter V provides comparisons of the results from each population. PYR pharmacokinetics in each population is best described by a two-compartment model with first order absorption and elimination from the central compartment. Although the same structural model is used, pharmacokinetics of PYR differs among the three populations. PYR is absorbed faster and more variably in patients. The weight-normalized total apparent volumes of distribution (V/F) in adult and pediatric patients are approximately 5 and 3 times larger than in healthy subjects. Adult and pediatric patients have a mean weight-normalized oral clearance (CL/F) approximately 2 times higher than healthy subjects but the drug is eliminated more slowly in patient populations due to a much larger V/F. The average elimination half-lives are 8, 11 and 18 days in healthy, pediatric and adult patient populations, respectively. Pharmacokinetic modeling suggests that lean body weight is an important predictor of apparent central volume (V2/F) in adult patients while actual body weight is a significant covariate of V2/F and CL/F in children. The parameters obtained from PPK modeling are plausible and estimated with acceptable precision. The final models are evaluated using a nonparametric bootstrap technique and visual predictive check. The final models are robust and adequately capture the overall pyronaridine pharmacokinetics. Further study in a broader patient population will be necessary to examine other covariates that influence pyronaridine pharmacokinetics.

The aim of this research was to determine the influence of route of administration, drug formulation and modified-liver metabolism on the pharmacokinetic and metabolic patterns of benzimidazole anthelmintics in ruminants. Both route of administration and formulation dramatically affected the bioconversion of netobimin (NTB) pro-drug, N-methoxycarbonyl-N$ sp prime$-(2-nitro-5-propylphenylthio)-${ rm N} sp{ prime prime}$-(2-ethyl sulphonic acid) guanidine, and the bioavailability and disposition kinetics of its active albendazole (ABZ) metabolites in both sheep and cattle. The efficacy of NTB conversion by the gastrointestinal (GI) microflora, was markedly lower after subcutaneous (SC) administration of NTB pro-drug compared with enteral administrations in both species. Although trisamine and zwitterion formulations of NTB were bioequivalent after SC treatment, the zwitterion suspension was two-fold more bioavailable in terms of ABZ metabolites, after oral administration to cattle. ABZ sulphoxide (ABZSO) and ABZ sulphone (ABZSO$ sb2$), the main metabolites found in plasma, were reversibly exchanged between plasma and GI compartments and concentrated in the abomasum. ABZ, ABZSO and ABZSO$ sb2$ were detected in the GI tract for 72 h post-NTB administration to cattle. In vitro, ABZ was oxidized into ABZSO and ABZSO$ sb2$ by liver microsomes and ruminal and ileal fluids. However, only ABZSO was reduced (back to ABZ) by these GI fluids. The rate of ABZ sulphoxidation by liver microsomes was significantly lower in cattle compared to sheep. However, while the oxidizing activity was greater in GI fluids of cattle, the reducing activity was prevalent in those of sheep. This was consistent with the higher ABZSO$ sb2$/ABZSO ratio and the markedly faster disposition of both metabolites in cattle compared to sheep. The co-administration of NTB with different oxidation-impairing compounds, largely methimazole (MTZ), in both species, resulted in an increased bioavailability and/o

Thesis (M.S.)--West Virginia University, 1999. / Title from document title page. Document formatted into pages; contains xvi, 100 p. : ill. Vita. Includes abstract. Includes bibliographical references (p. 98-99).

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