Liquid chromatographic assay of nifedipine in human plasma and its application to pharmacokinetic studies.

A highly sensitive, selective and reproducible reversed-phase high-performance liquid chromatographic method has been developed for the determination of nifedipine in human plasma with minimum sample preparation. The method is sensitive to 3 ng/ml in plasma, with acceptable within- and between-day reproducibilities and linearity (r2 > 0.99) over a concentration range from 10-200 ng/ml. Acidified plasma samples were extracted using diethyether containing diazepam as internal standard and chromatographic separation was accomplished on C18 column using a mobile phase consisting of acetonitrile, methanol and water (35:17:48, v/v). The within-day precision ranged from 2.22 to 4.64% and accuracy ranged from 102.4-106.4%. The day-to-day precision ranged from 2.34-7.07% and accuracy from 95.1-100.1%. The relative recoveries of nifedipine from plasma ranged from 91.0-107.3% whereas extraction recoveries were 88.6-93.3%. Following eight 6-week freeze-thaw cycles, nifedipine in plasma samples proved to be stable with accuracy ranging from 0.64 to 3.0% and precision ranging from 3.6 to 4.15%. Nifedipine was also found to be photostable for at least 120 min in plasma, 30 min in blood and for 60 min in aqueous solutions after exposure to light. The method is sensitive and reliable for pharmacokinetic studies and therapeutic drug monitoring of nifedipine in humans after the oral administration of immediate-release capsules and sustained-release tablets to five healthy subjects.

Influence of piperacillin on the pharmacokinetics of methotrexate and 7-hydroxymethotrexate.

The influence of concomitant administration of piperacillin (PIP) on the pharmacokinetic parameters of methotrexate (MTX) and 7-hydroxymethotrexate (7-OH-MTX) was studied in rabbits. Six rabbits received an initial i.v. bolus (0.21 mg kg(-1)) followed by a constant-rate i.v. infusion of the drug (5 microg min(-1) kg(-1)) for 240 min. The PIP dose (30 mg kg(-1)) was repeated every 30 min until the end of the infusion period. The control group consisted of four rabbits treated the same way except for the addition of PIP. There were significant increases in the mean residence times found for MTX (MRTinf) and 7-OH-MTX (MRTm,inf) following PIP administration. Concomitant administration of PIP with MTX also produced significant 1.5- and 2.8-fold increases in the area under the curve of MTX and 7-OH-MTX, respectively. The total body clearance of MTX and the operative total body clearance of 7-OH-MTX significantly decreased, but in a less than proportional manner. The study demonstrates that the interaction between MTX and PIP is mainly due to the reduced clearance of both MTX and 7-OH-MTX combined with a slight increase in the formation clearance of the metabolite.

High-performance liquid chromatographic determination of furosemide in plasma and urine and its use in bioavailability studies.

A sensitive, selective and efficient reversed-phase high-performance liquid chromatographic (HPLC) method is reported for the determination of furosemide in human plasma and urine. The method has a sensitivity limit of 5 ng/ml in plasma, with acceptable within- and between-day reproducibilities and good linearity (r2>0.99) over a concentration range from 0.05 to 2.00 microg/ml. The one-step extract of furosemide and the internal standard (warfarin) from acidified plasma or urine was eluted through a muBondapak C18 column with a mobile phase composed of 0.01 M potassium dihydrogenphosphate and acetonitrile (62:38, v/v) adjusted to pH 3.0. Within-day coefficients of variation (C.V.s) ranged from 1.08 to 8.63% for plasma and from 2.52 to 3.10% for urine, whereas between-day C.V.s ranged from 4.25 to 10.77% for plasma and from 5.15 to 6.81% for urine at three different concentrations. The minimum quantifiable concentration of furosemide was determined to be 5 ng/ml. The HPLC method described has the capability of rapid and reproducible measurement of low levels of furosemide in small amounts of plasma and urine. This method was utilized in bioavailability/pharmacokinetic studies for the routine monitoring of furosemide levels in adults, children and neonate patients.

Comparative pharmacokinetics and pharmacodynamics of furosemide in Middle Eastern and in Asian subjects.

The pharmacokinetics and pharmacodynamics of a single oral dose of 40 mg furosemide has been compared in 11 healthy Middle Eastern Arabs with 12 Asian subjects under fasting conditions. There were no significant differences (p > 0.05) between the 2 ethnic groups in either the area under the plasma concentration time curve (AUC) or the time to maximal plasma concentration (tmax). The elimination half-life was significantly higher (p < 0.05) in Middle Eastern subjects (2.9+/-0.7 h) than in Asian subjects (2.2+/-0.6 h), while the maximal plasma concentration (Cmax) in Asian subjects (1,087+/-262 ng/ml) was significantly higher (p < 0.05) compared with Middle Eastern Arabs (776+/-163 ng/ml). The mean residence time (MRT) and the operative apparent volume of distribution (Vd/F) were significantly greater in Middle Eastern Arabs (4.5+/-0.9 h and 54.1+/-14.91) than in Asian subjects (3.6+/-0.8 h and 38.6+/-16.51). The difference between them in (Vd/F) abolished (p > 0.05) when corrected for body weight. The mean cumulative urinary excretion of furosemide in 8 h was 5.6 mg (range 1.6-15.2 mg) for Arabs and 6.1 mg (range 2.1-15.9 mg) for Asians. The relationships between furosemide-induced diuresis and furosemide, sodium, potassium, calcium, magnesium and chloride excretion rates appeared as a clockwise hysteresis loop indicating the development of tolerance during the course of drug action in both ethnic groups. No statistically significant differences (p > 0.05) were observed in the cumulative amounts excreted in urine of these electrolytes or their excretion rates between Arabs and Asians. The relationships between urinary excretion rates of sodium, potassium, calcium, magnesium, and chloride were linear with almost identical slopes for Arabs and Asians in each relationship.

Atom level electrotopological state indexes in QSAR: designing and testing antithyroid agents.

PURPOSE: To design antithyroid agents with less side effects, the electrotopological-state (E-state) indexes of thiourylene moiety (SN&S) was utilized as a guideline to develop five acrylic thiourylene-type compounds with reduced antioxidant property. METHODS: These agents were synthesized and screened for antithyroid activity in rats using 125I-thiocyanate discharge technique. In addition, chemiluminescence studies on the activated polymorphonuclear leukocytes (PMNLs) were also conducted to reveal antioxidant properties of the tested compounds. RESULTS: A linear relationship between the in vitro literature value of the formation constants of thiourylene-type compounds with iodine (Kc) and the SN&S was observed and utilized in designing those agents. At least one of the compounds (abouthiouzine) was found to have a potential value as an antithyroid agent. The relative efficacy of abouthiouzine [1-n-butyl-3(isonicotinamido)-2-thiourea], after equimolar dose, was 102% and 51.5% of that of propylthiouracil with respect to the rate of 125I-discharge and 125I-uptake, respectively. In addition, chemiluminescence studies on PMNLs revealed that abouthiouzine has slight oxidant property. Such properties may provide advantages in avoiding the iatrogenic hypothyroidism and antithyroid-induced immunological reactions. CONCLUSIONS: The E-state approach provides guidelines to economize efforts and cost of designing new antithyroid drugs.

Comparative study of Saudi-marketed products and US drug labeling.

Drug package inserts from ten nonsteroidal antiinflammatory drugs marketed in Saudi Arabia were compared with their corresponding US labels to determine possible differences in their information content. These variations were assessed with special regard to the number of words used and the type of the information provided. The study showed that inserts of Saudi-marketed products generally conveyed limited and incomplete information. Possible adverse reactions, drug--drug interactions, and date of revision often were not included, although this information was present on the corresponding US labels. Comparisons of the package inserts of the same product from various pharmaceutical companies show wide variations in the amount of information provided. Determining the minimal level of information that must be included by the manufacturer in the package insert and the establishment of firm international guidelines by the World Health Organization could effectively reduce such variations.