Pharmacokinetics of ritodrine diastereomers in patients pregnant with singletons and twins.

OBJECTIVE: The chiral pharmacokinetics and pharmacodynamics of ritodrine in patients pregnant with singletons and twins were investigated to determine the optimal use of ritodrine. METHODS: Eight and 20 patients with threatened preterm delivery of singletons and twins, respectively, were infused with ritodrine diastereomers. Serum concentrations of the drug were then measured using a newly developed method of chiral high-performance liquid chromatography. RESULTS: Almost double the dosage of racemic ritodrine was required to prolong pregnancies with twins compared with those of singletons (2.20 +/- 1.06 vs. 1.24 +/- 0.36 microg/min per kilogram; p < 0.0001). The mean ratios of (-)-ritodrine to (+)-ritodrine in singleton and twin pregnancies were 1.17 +/- 0.10 and 1.16 +/- 0.10, respectively. However, the serum concentration and dosage ratio (C/D ratio) of (-)-ritodrine as significantly higher than that of (+)-ritodrine (p < 0.0001), whereas the clearance of (-)-ritodrine was significantly lower than that of (+)-ritodrine (p < 0.0001). A comparison of the gestation period (weeks) and diastereomer clearance did not reveal significant regression in the total analysis of the data obtained from singleton and twin pregnancies. CONCLUSION: These results indicate that the clinical effectiveness of ritodrine diastereomers should be evaluated and that administration guidelines should be established based upon serum concentrations so that ritodrine can be more effectively administered to pregnant patients carrying either singletons or twins.

Ritodrine pharmacokinetics in twin pregnancy patients.

OBJECTIVES: To establish a rational ritodrine therapy in relation to serum ritodrine concentration, we examined 14 twin pregnancy patients and determined their pharmacokinetic data. METHODS: We measured serum concentrations of ritodrine in twin pregnancy patients using high-performance liquid chromatography (HPLC). RESULTS: The twin pregnancy patients all exhibited linear ritodrine pharmacokinetic profiles. There was a statistically significant but slight negative correlation between gestation period and ritodrine clearance (y=-0.038x+2.75, r=0.349, p<0.001) among all patients. However, when analyzed on an individual basis, there was a high correlation found in three of the 14 patients. CONCLUSION: Due to a decrease in total body clearance in three of the 14 patients, overall serum concentration of ritodrine increased at the end of the pregnancies. To further characterize ritodrine kinetics, additional studies are needed to determine an effective and safe therapy for ritodrine use in twin pregnancy patients.

Effects of aluminum hydroxide and famotidine on bioavailability of tosufloxacin in healthy volunteers.

This study was designed to determine the influence of aluminum hydroxide and famotidine on the bioavailability of tosufloxacin. Coadministration of aluminum hydroxide reduced the bioavailability of tosufloxacin by 31.6% (P < 0.05). Famotidine did not alter tosufloxacin absorption. To avoid potential treatment failures, the concurrent use of tosufloxacin and aluminum hydroxide should be avoided altogether.

Pharmacokinetics of nicardipine enantiomers in healthy young volunteers.

OBJECTIVES: The present study was conducted to compare pharmacokinetic behaviors of nicardipine enantiomers given in different doses with different formulations of racemic nicardipine in healthy volunteers. METHODS: One or two 20-mg racemic nicardipine tablets, and a 40-mg sustained-release capsule of nicardipine were administered to eight healthy volunteers in a crossover fashion and pharmacokinetic parameters were evaluated. Enantiomer concentrations were determined by GC-MS combined with chiral stationary phase HPLC. RESULTS AND CONCLUSIONS: Serum concentration of (+)-nicardipine was approximately 2-3 times higher than that of (-)-nicardipine in 20- and 40-mg doses of conventional formulations and a non-linear increase in bioavailability with dose was demonstrated. The value for AUC of (+)-nicardipine was approximately 2.3-2.8 times greater than that of the (-)-nicardipine (P < 0.05) when 20 and 40 mg racemic nicardipine were administered in a conventional preparation. Relative bioavailability of the sustained-release preparation vs the conventional preparation was 28% and 44% for (+)- and (-)-nicardipine, respectively, for the 40-mg dose.

Effect of activated charcoal and atropine on absorption and/or exsorption of organophosphorus compounds in rats.

Effects of activated charcoal and atropine for the removal of organophosphorus compounds, which remain in the gastrointestinal tract or have already been absorbed into the systemic circulation, were investigated in rats. Activated charcoal extensively adsorbed the organophosphates fenitrothion, tolelofos methyl, piperophos and salithion, and its immediate administration after oral ingestion of fenitrothion remarkably reduced serum fenitrothion levels, but had no effect on the serum levels of the compound which had been absorbed from the gastrointestinal tract. Thus, all of the organophosphorus compounds were poorly exsorbed (0.002-0.39% of the dose in 120 min) from the blood into the intestinal lumen probably due to their extensive protein binding and large distribution volumes. Atropine inhibited absorption of fenitrothion in the perfusion in-situ and also delayed the absorption of the compound in-vivo, but had no significant effect on exsorption of fenitrothion. The serum fenitrothion levels on treatment with both atropine and charcoal significantly decreased compared with those of the control. We conclude that, oral activated charcoal will not be able to enhance the elimination of organophosphorus compounds which have already been absorbed into the systemic circulation, but constituted useful method for the removal of the compounds remaining in the gastrointestinal tract because of its excellent adsorptive capacity.

Transport of levofloxacin in a kidney epithelial cell line, LLC-PK1: interaction with organic cation transporters in apical and basolateral membranes.

The interactions of levofloxacin, a pyridonecarboxylic acid antibacterial drug, with the organic cation transport systems expressed in a pig kidney epithelial cell line, LLC-PK1, were examined. The transcellular transport of tetraethylammonium was remarkably inhibited by levofloxacin, accompanied by a marked increase in the cellular accumulation of tetraethylammonium in the LLC-PK1, monolayers grown on collagen-coated membrane filters. The results obtained by efflux and uptake of tetraethylammonium revealed that levofloxacin drastically inhibited the apical transport activity rather than the basolateral uptake of tetraethylammonium. Under conditions in which the apical efflux of tetraethylammonium was blocked by pretreatment with p-chloromercuribenzene sulfonate, levofloxacin showed a moderate inhibitory effect against the basolateral uptake of tetraethylammonium. Transepithelial flux of levofloxacin from the basolateral side to the apical side was much greater than the flux in the opposite direction. The flux of levofloxacin was influenced by the apical side pH, resulting in a decreased cellular accumulation by lowering pH. The basal-to-apical transport and cellular accumulation of levofloxacin were not inhibited by either tetraethylammonium or cimetidine. These results suggested that levofloxacin interacts with the apical H+/organic cation antiport system to a greater extent than with the basolateral system. However, transcellular transport of levofloxacin would be mediated by the transport systems which are distinct from the systems for tetraethylammonium in LLC-PK1 cells.

Determination of (+)- and (-)-nicardipine concentrations in human serum and their correlation with the antihypertensive effect after oral administration of racemic nicardipine.

Serum (+)- and (-)-nicardipine concentrations were determined after oral administration of racemic nicardipine, and the relationship between the concentration of each enantiomer and the percentage change in blood pressure was investigated. Serum concentrations of (+) and (-)-nicardipine were assayed separately by a method combining high-performance liquid chromatography (HPLC) with gas chromatography - mass spectrometry (GS-MS). Linear relationships were found with serum concentrations of 0.25-80 mg x ml(-1) for both enantiomers of nicardipine with correlation coefficients of greater than 0.999. A single oral dose of 40 mg racemic nicardipine was given to 15 patients with essential hypertension. Serum (+)-nicardipine concentration was 2-3 times higher than the concentration of (-)-nicardipine 1, 2, and 3 after drug administration. The logarithmically transformed value of the serum (+)-nicardipine concentration was inversely correlated with the percentage change in systolic blood pressure, the correlation being statistically significant 1 and 2 h after drug administration, and also inversely correlated with the percentage change in diastolic blood pressure 1, 2 and 3 h after drug administration. However, the logarithmically transformed value of serum (-)-nicardipine showed no significant correlations with the percentage change in either systolic or diastolic blood pressure.

Effect of milk on absorption of norfloxacin in healthy volunteers.

The authors studied the effect of milk on the bioavailability of norfloxacin in six healthy male volunteers in a randomized crossover trial. After an overnight fast, 200 mg of norfloxacin was given with 200 mL of water or milk. Area under the curve (AUC) of norfloxacin with milk was significantly (P < 0.01) smaller than that with water. The mean peak serum concentration was decreased to 60% after oral administration of norfloxacin with milk (P < 0.01). The apparent volume of distribution at central compartment (Vc/f) value of norfloxacin was significantly (P < 0.05) increased with milk. Milk exhibits a clinically significant effect on norfloxacin absorption.

Inhibitory effects of procainamide and probenecid on renal excretion of sultopride enantiomers in rats.

The effects of the coadministration of procainamide and probenecid on the pharmacokinetic behavior of sultopride, an antipsychotic agent, after intravenous administration were studied with rats. The areas under the concentration-time curve for and renal clearances of (+)-sultopride and (-)-sultopride, which exist as organic cations under physiological pH conditions, were significantly decreased (p < 0.01) by the coadministration of procainamide, an organic cation under physiological pH conditions. The renal clearance of (-)-sultopride was partially decreased (p < 0.05) by the coadministration of probenecid, an organic anion under physiological pH conditions. The results suggest that drug-drug interactions between organic cations and organic anions occur to a certain extent during the tubular secretion process in rats.

Disposition of enantiomers of sultopride in a human, rats and rabbits.

Pharmacokinetics of sultopride enantiomers was examined following a single dose in a human, rabbits and rats. Pharmacokinetic profiles were similar between (+)- and (-)-enantiomers of sultopride in human, whereas the serum concentrations of (-)-sultopride were slightly higher than those of (+)-sultopride after i.v. administration of 50 mg/kg of racemic sultopride to rats and rabbits.

Disposition of enantiomers of sulpiride in humans and rats.

Pharmacokinetics of sulpiride enantiomers after intravenous administration of (+/-)-, (+)-, and (-)-sulpiride was examined in humans and rats. Pharmacokinetics profiles were similar in (+)- and (-)-enantiomers after intravenous administration of (+/-)-sulpiride. Metabolic inversion at a chiral centre was not observed after intravenous administration of each enantiomer in rats.

Stereoselective analysis of the disposition of tosufloxacin enantiomers in man.

The pharmacokinetics of tosufloxacin enantiomers after oral administration of racemic tosufloxacin were examined in healthy volunteers. Only small differences were observed in time to peak concentration (2.6 +/- 0.3 [mean +/- SEM] h for (+)-tosulfoxacin vs 2.4 +/- 0.2 h for (-)-tosufloxacin), elimination half-life (3.61 +/- 0.24 h vs 3.49 +/- 0.23 h), and area under the curve (2.78 +/- 0.19 h.micrograms/ml vs 2.87 +/- 0.19 h.micrograms/ml); however, peak concentration (0.40 +/- 0.03 microgram/ml vs 0.44 +/- 0.03 microgram/ml), renal clearance (226 +/- 10 ml/min vs 202 +/- 10 ml/min), and urinary recovery (35.4 +/- 2.2% vs 32.4 +/- 1.9%) differed significantly between enantiomers.

Determination of sultopride and tiapride in serum by gas chromatography using a surface ionisation detector.

A sensitive and selective method has been developed for the determination of sultopride and tiapride in serum using gas chromatography with a surface ionisation detector. No interfering peaks from endogenous substances were observed. The method showed good reproducibility and accuracy, and the standard curve was linear up to 2 micrograms/ml with a correlation coefficient of 0.999. This method is applicable to pharmacokinetic studies and therapeutic drug monitoring of sultopride and tiapride.

Effect of food on the bioavailability of bromazepam following oral administration in healthy volunteers.

The effect of food on the rate and extent of bioavailability of bromazepam was examined in seven normal volunteers following a single oral dose of 10 mg bromazepam with 200 ml of water in the fasting and non-fasting states. Plasma concentrations of bromazepam were measured by high pressure liquid chromatography. A tmax value in a non-fasting state was prolonged from 2.3 +/- 0.3 (mean +/- S.E.M.) to 2.8 +/- 0.6 h but not significantly different (p greater than 0.05) whereas a Cmax value was significantly (p less than 0.05) decreased from 259 +/- 12.7 (mean +/- S.E.M.) to 169 +/- 13.9 ng/ml. The area under the plasma concentration-time curve in the non-fasting state was also significantly (p less than 0.05) decreased from 1844 +/- 145 (mean +/- S.E.M.) to 1233 +/- 98.1 ng.h/ml after oral administration of bromazepam.

Effects of H1-receptor stimulation on coronary arterial diameter and coronary hemodynamics in humans.

Effects of H1-receptor stimulation on coronary arterial diameter and coronary hemodynamics were examined in 11 patients with angiographically normal coronary arteries and without variant angina or resting angina. Selective H1-receptor stimulation was achieved by infusing histamine into the left coronary artery at a rate of 2.0 micrograms/min for 5 minutes after pretreatment with cimetidine (25 mg/kg). Plasma histamine concentration in the coronary sinus, coronary sinus blood flow, heart rate, and aortic pressure were measured before, during, and after the histamine infusion. Coronary arterial diameter was measured by cinevideodensitometric analysis of coronary arteriograms performed before and immediately after the histamine infusion. During the histamine infusion, plasma histamine concentration in the coronary sinus increased from 0.33 +/- 0.06 to 5.86 +/- 0.71 ng/ml (p less than 0.01); coronary sinus blood flow increased from 98 +/- 12 to 124 +/- 13 ml/min (p less than 0.01), and coronary vascular resistance decreased from 1,113 +/- 117 to 851 +/- 91 mm Hg.min/l (p less than 0.01). Heart rate and aortic pressure remained unchanged. The mean luminal diameters of the proximal, middle, and distal left anterior descending artery increased by 9.4 +/- 3.6% (p less than 0.05), 19.2 +/- 3.8% (p less than 0.001), and 31.5 +/- 5.6% (p less than 0.001), respectively, after the histamine infusion. The mean luminal diameters of the proximal, middle, and distal left circumflex artery increased by 15.2 +/- 3.6% (p less than 0.01), 17.5 +/- 5.2% (p less than 0.01), and 20.6 +/- 4.3% (p less than 0.001), respectively, after the histamine infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Removal of famotidine by haemodialysis in elderly anuric patients.

The effect of haemodialysis on the pharmacokinetics of oral famotidine has been studied in five elderly anuric patients. Famotidine 20 mg was administered in a cross-over design to patients on and not on haemodialysis. The elimination rate constant of haemodialysis (k) was 4.6-fold larger than the systemic elimination rate constant (ke). Although the mean maximum serum concentration of famotidine during haemodialysis (141.5 ng.ml-1) was not significantly lower than that without haemodialysis (195.6 ng.ml-1), the AUC up to 5 h during haemodialysis was significantly decreased to 58.1% of the value without it. The data suggest that famotidine is dialysable by haemodialysis.

The inhibitory effect of probenecid on renal excretion of famotidine in young, healthy volunteers.

Effects of coadministration of probenecid on pharmacokinetic behaviors of famotidine, an H2-receptor antagonist, after oral administration, were studied in eight young, healthy volunteers. They received an oral 20 mg dose of famotidine with and without coadministration of oral 1500 mg doses of probenecid. The mean area under the serum famotidine concentration-time curve up to 10 hours was increased by coadministration of probenecid from 424 +/- 19 (SEM) to 768 +/- 39 ng.hr/ml. The mean urinary excretion rate of unchanged famotidine, the mean amount of unchanged famotidine excreted in urine up to 24 hours and mean renal clearance were decreased by coadministration of probenecid. The mean tubular secretion clearance of famotidine was decreased from 196.2 +/- 21.4 to 22.0 +/- 4.2 ml/min. These data suggest that probenecid, which is a classical inhibitor of renal tubular secretion of organic anions, inhibits the renal tubular secretion of famotidine, which exists partly in a cationic form under physiological pH conditions.

Physiologic and metabolic aspects of anticonvulsants.

A great number of anticonvulsants are available for treating these different types of epilepsy. Therapeutic drug monitoring has been favored as the method for controlling drug concentrations in the plasma and preventing untoward effects. When these anticonvulsants are prescribed to treat epilepsy in children, careful monitoring is most important because drug metabolism varies depending on maturation and development of body functions. Molecular approaches are also important to elucidate the effectiveness of the drugs for treatment of different seizure disorders and should contribute to a better understanding of body functions.

Rapid and sensitive determination of aprindine in serum by gas chromatography using a surface ionization detector.

A rapid and highly sensitive method for the determination in serum of aprindine, an antiarrhythmic drug, was developed employing gas chromatography with a surface ionization detector. No interfering peak from endogenous substances appeared when an organic phase was directly injected into the system after single extraction from a serum sample. A standard curve obtained was linear up to the serum level of 6 micrograms/ml, and the limit of sensitivity was 16 pg. The method described is applicable to routine therapeutic monitoring of serum concentrations of aprindine.