The pharmacokinetics of β-cyclodextrin and hydroxypropyl-β-cyclodextrin in the rat

Hydroxypropyl-β-cyclodextrin was analyzed by HPLC using postcolumn complexation with phenolphthalein and negative colorimetric detection, with a detection limit of 20 μg/ml. The pharmacokinetics of β-cyclodextrin and of hydroxypropyl-β-cyclodextrin were studied after intravenous administration to permanently cannulated rats. The pharmacokinetic behavior of both cyclodextrins was similar to that of inulin, showing rapid distribution over extracellular fluids. Elimination occurred through glomerular filtration. When a dose of 200 mg/kg β-cyclodextrin was administered the elimination rate was decreased, probably as a result of nephrotoxicity of β-cyclodextrin. Within 24 hr after administration most of the cyclodextrin dose was recovered unchanged in urine. After oral administration, only insignificant amounts of intact β-cyclodextrin were absorbed from the gastrointestinal tract

Bioananalysis of captopril: two sensitive high-performance liquid chromatographic method with pre- or postcolumn fluorescent labeling

This study describes the development and comparison of two HPLC methods for the analysis of the antihypertensive drug captopril. The first method is based on a precolumn derivatization of captopril with the fluorescent label monobromobimane (MBB), The second method is based on a postcolumn reaction with the fluorescent reagent o-phthaldialdehyde (OPA). Since the disulfide metabolites of captopril can be reconverted to the active drug in vivo, the bioanalysis of captopril should involve both the determination of its free thiol form (free captopril) and the total amount of free thiol and reducible disulfides (total captopril). For total captopril analysis, disulfides were reduced with tributylphosphine (TBP) prior to protein precipitation, Since the reducing agent interfered with the MBB derivatization reaction, this method was not suitable for total captopril analysis. Both methods were validated for the bioanalysis of free captopril in human plasma. After removal of plasma proteins, samples were analyzed without an additional extraction procedure. The limit of quantitation in plasma was 12.5 ng/ml for the MBB method (limit of detection 30 pg) and 25 ng/ml for the OPA method (limit of detection 50 pg). The OPA method was also validated for total captopril analysis in human plasma and urine. The limit of quantitation was 25 ng/ml in plasma and 250 ng/ml in urine (limit of detection 50 pg). We conclude that for the analysis of free captopril the precolumn MBB method is superior to the OPA method since only the derivatization reaction has to be carried out immediately. The postcolumn OPA method is especially suitable for the analysis of total captopril since reducing reagents and high concentrations of endogenous thiols do not interfere with the derivatization reaction

Bioananalysis of captopril: two sensitive high-performance liquid chromatographic method with pre- or postcolumn fluorescent labeling

This study describes the development and comparison of two HPLC methods for the analysis of the antihypertensive drug captopril. The first method is based on a precolumn derivatization of captopril with the fluorescent label monobromobimane (MBB), The second method is based on a postcolumn reaction with the fluorescent reagent o-phthaldialdehyde (OPA). Since the disulfide metabolites of captopril can be reconverted to the active drug in vivo, the bioanalysis of captopril should involve both the determination of its free thiol form (free captopril) and the total amount of free thiol and reducible disulfides (total captopril). For total captopril analysis, disulfides were reduced with tributylphosphine (TBP) prior to protein precipitation, Since the reducing agent interfered with the MBB derivatization reaction, this method was not suitable for total captopril analysis. Both methods were validated for the bioanalysis of free captopril in human plasma. After removal of plasma proteins, samples were analyzed without an additional extraction procedure. The limit of quantitation in plasma was 12.5 ng/ml for the MBB method (limit of detection 30 pg) and 25 ng/ml for the OPA method (limit of detection 50 pg). The OPA method was also validated for total captopril analysis in human plasma and urine. The limit of quantitation was 25 ng/ml in plasma and 250 ng/ml in urine (limit of detection 50 pg). We conclude that for the analysis of free captopril the precolumn MBB method is superior to the OPA method since only the derivatization reaction has to be carried out immediately. The postcolumn OPA method is especially suitable for the analysis of total captopril since reducing reagents and high concentrations of endogenous thiols do not interfere with the derivatization reaction

Distribution and Elimination of the Glycosidase Inhibitors 1-Deoxymannojirimycin and N-Methyl-1-Deoxynojirimycin in the Rat in Vivo

We studied the pharmacokinetics of two synthetic derivatives of 1-deoxynojirimycin in the rat after intravenous administration. The mannosidase IA/B inhibitor 1-deoxymannojirimycin and the glucosidase inhibitor N-methyl-1-deoxynojirimycin exhibited minimal plasma protein binding and showed a rapid biphasic plasma disappearance, with an initial t1/2 of 3.0 and 4.5 min, respectively, and a terminal t1/2 of 51 and 32 min, respectively. For both compounds renal excretion is the major route of elimination. After 120 min, 52% of the dose of 1-deoxymannojirimycin and 80% of the dose of N-methyl-1-deoxymannojirimycin was recovered unchanged from the urine, whereas only 4.9 and 0.2%, respectively, of the dose was excreted in bile. Urinary clearance of 1-deoxymannojirimycin was similar to the glomerular filtration rate. In contrast, urinary clearance of N-methyl-1-deoxynojirimycin was two to three times higher than the glomerular filtration rate, indicating active tubular secretion. Ligation of the renal vessels decreased the total-body clearance of 1-deoxymannojirimycin and N-methyl-1-deoxynojifimycin 18- and 24-fold, respectively. Neither alkalinization of the urine by infusion of bicarbonate solutions nor forced diuresis altered the renal excretion rate of these compounds, implying the absence of tubular reabsorption. At 120 min, the amounts of 1-deoxymannojirimycin in liver and kidney were 2.1 and 1.1% of the dose, respectively, while small intestine, stomach, and heart contained only 0.9, 0.6 and 0.1%. Less than 1% of the dose of N-methyl-1-deoxynojirimycin was found in the collected organs 2 hr after injection. At the same time point, the kidney/plasma concentration ratio of N-methyl-1-deoxynojirimycin was 10-fold higher than in other tissues, whereas for 1-deoxymannojirimycin it was only 2- to 3-fold higher in kidney, indicating a more persistent general tissue retention of 1-deoxymannojirimycin