Urinary excretion kinetics of p-nitrophenol following oral administration of parathion in the rabbit

The urinary excretion kinetics of p-nitrophenol were studied in rabbits following oral administration of parathion at a dose of 3 mg/kg. Elimination of p-nitrophenol began rapidly, and of the total amount excreted during the study period, 46% was excreted in the first 3 h; 85% was excreted at 6 h after administration of the pesticide. The mean maximum excretion rate of p-nitrophenol was 111.15±61.02 g/h reached in a time of 0.77±0.26 h. The formation and disappearance rate constants of the metabolite were 2.85±2.80 h^–1 and 0.80±0.28 h^–1, respectively. A linear relationship was observed between the plasma concentrations of parathion and the urinary excretion rate of p-nitrophenol.     

Stereospecific hydroxylation of nortriptyline in man in relation to interindividual differences in its steady-state plasma level

Summary Thecis andtrans isomers of 10-hydroxynortriptyline (10-OH-NT), the major metabolite of nortriptyline (NT) in man, have been separated and quantitated in urine from 6 healthy volunteers who received NT orally, 0.4 mg/kg body weight, three times daily. The isomers were separated by preparative thin layer chromatography and quantitatively determined by gas chromatography as the 10,11-dehydronortriptyline heptafluorobutyryl derivative. The structure of these derivatives producedin vitro was confirmed by gas chromatography — mass spectrometry. Less than 1% of totally excreted 10-OH-NT was accounted for as 10,11-dehydronortriptyline. — Despite interindividual differences in the mean steady-state plasma concentration of NT, the ratio between the two isomers was constant in all subjects (1:4–5). The isomers were both optically active and circular dichroism spectra showed that the asymmetric carbon atoms in the two compounds have different configurations. — It is concluded that NT undergoes stereospecific hydroxylation in man and that there is no correlation between the mean steady-state plasma concentration of NT and the proportion of thecis andtrans isomers formed.     

The absorption of [G-3H]-acetylglycyrrhetate after oral administration to rats.

A tritium-labelled form of aluminium acetylglycyrrhetate has been synthesised by catalytic exchange with tritiated water. An oral dose of aluminium [3H]-acetylglycyrrhetate to rats was mainly excreted in the faeces (a mean of 73%). A mean of 4% was excreted in the urine and after five days 17% of the radioactivity was retained in the carcass. The amounts of non-volatile (drug-related radioactivity excreted in faeces and urine during five days were 65% and 3%, respectively, while 6% was retained in the carcass. The total amount of tritiated water produced was 24% of the dose. Experiments in rats with cannulated bile ducts indicated that much of the faecal radioactivity represented unabsorbed drug. 15% of an oral dose was eliminated in bile during 2 days. A minimum value for the extent of absorption of an oral dose was estimated as 21%. Plasma levels of radioactivity were very low and peak levels of drug-related radioactivity were reached at 30 min and represented about 0.2% of the dose in total plasma.     

Regional and systemic serum concentrations of 5-fluorouracil after portal and intravenous infusion: An experimental study in dogs

The serum and urinary concentrations of 5-FU after continuous portal and jugular infusion have been followed by means of a highly sensitive microbiological assay method. Our data indicate that more than 90% of 5-FU was eliminated in the liver after continuous portal infusion of 0.625 mg × kg ^–1 × hr ^–1 ,corresponding to a dose of 15 mg × kg ^–1 ×24 hr ^–1 .Negligible amounts of intact 5-FU were excreted into the bile, and the urinary excretion was only a few percent of the amount infused. The arterial concentration was on average tenfold higher during the continuous jugular infusion than after the continuous portal infusion, indicating that the route of administration has a pronounced effect on the disposition of 5-FU. Twenty-three percent of the jugular dose reached the liver; 77% was degraded by extrahepatic metabolism. Of these, degradation in the prehepatic splanchnic area accounted for 15%.This research was supported by the Swedish Cancer Society (Projects No. 512-B74-04X and 512-B75-05X).     

Absorption,metabolism and elimination of strophanthus glycosides in man

Summary In 33 healthy male volunteers, given a single oral and intravenous dose of cymarin (k-strophanthin-), k-strophanthoside (k-strophanthin-) and ouabain (g-strophanthin), enteral absorption and renal excretion of these glycosides and their metabolites were investigated by radioimmunoassay and HPLC. Cymarin was absorbed at 47% of the given dose. After intravenous injection 46% and after oral administration 21% of the given dose, i.e. the total amount as detected by radioimmunoassay which consisted of the unchanged glycoside and its metabolites, were excreted by the kidneys mainly as conjugated metabolites. The half-life of elimination, calculated from the total excreted amount was 13 h (i.v.) and 23 h (p.o.), respectively. k-Strophanthoside was absorbed at 16% of the given dose. After i.v.-injection 73% of the given dose was excreted by the kidneys with a half-life of elimination of 99 h. From this total amount about 70% was excreted as the unchanged drug, the remaining 30% as various metabolites. After oral administration 11% of the given dose were excreted with a half-life of elimination of 22 h. 80% of this amount consisted mainly of conjugated k-strophanthoside and conjugated metabolites as k-strophanthin-, cymarin, k-strophanthidin, cymarol and k-strophanthidol. Only 6% was excreted as the unchanged drug. Ouabain was absorbed after oral administration to a minimum of 1.4%. Given intravenously a total renal excretion of 33% of the given dose with a half-life of elimination of 23 h was measured. Of this 80% was unchanged ouabain. The remaining 20% seemed to be conjugated metabolites which could not be exactly identified.Supported by the Deutsche Forschungsgemeinschaft, Sonderforschungsbereich Düsseldorf (SFB 30)     

Di(2-ethylhexyl)phthalate (DEHP) metabolites in human urine and serum after a single oral dose of deuterium-labelled DEHP

Human metabolism of di(2-ethylhexyl)phthalate (DEHP) was studied after a single oral dose of 48.1 mg to a male volunteer. To avoid interference by background exposure the D4-ring-labelled DEHP analogue was dosed. Excretion of three metabolites, mono(2-ethyl-5-hydroxyhexyl)phthalate (5OH-MEHP), mono(2-ethyl-5-oxohexyl)phthalate (5oxo-MEHP) and mono(2-ethylhexyl)phthalate (MEHP), was monitored for 44 h in urine and for 8 h in serum. Peak concentrations of all metabolites were found in serum after 2 h and in urine after 2 h (MEHP) and after 4 h (5OH-MEHP and 5oxo-MEHP). While the major metabolite in serum was MEHP, the major metabolite in urine was 5OH-MEHP, followed by 5oxo-MEHP and MEHP. Excretion in urine followed a multi-phase elimination model. After an absorption and distribution phase of 4 to 8 h, half-life times of excretion in the first elimination phase were approximately 2 h with slightly higher half-life times for 5OH- and 5oxo-MEHP. Half-life times in the second phase—beginning 14 to 18 h post dose—were 5 h for MEHP and 10 h for 5OH-MEHP and 5oxo-MEHP. In the time window 36 to 44 h, no decrease in excreted concentrations of 5OH- and 5oxo-MEHP was observed. In the first elimination phase (8 to 14 h post dose), mean excretion ratios of MEHP to 5oxo-MEHP and MEHP to 5OH-MEHP were 1 to 1.8 and 1 to 3.1. In the second elimination phase up to 24 h post dose mean excretion ratios of MEHP to 5oxo-MEHP to 5OH-MEHP were 1 to 5.0 to 9.3. The excretion ratio of 5OH-MEHP to 5oxo-MEHP remained constant through time at 1.7 in the mean. After 44 h, 47% of the DEHP dose was excreted in urine, comprising MEHP (7.3%), 5OH-MEHP (24.7%) and 5oxo-MEHP (14.9%).     

Dose proportionality of nadolol pharmacokinetics after intravenous administration to healthy subjects

Summary To support the increasing use of intravenous -blockers during cardiovascular emergency and surgery, dose proportionality of pharmacokinetics of nadolol was evaluated after intravenous administration of ¹⁴C-nadolol at doses of 1, 2 and 4 mg to nine healthy volunteers. There were no observed differences in the excretion or the pharmacokinetics of nadolol with respect to the dose administered. Over a 72-h period after drug administration, an average of about 60% of the dose was excreted in the urine and about 15% was excreted in the feces. The range of values for total body clearance (219 to 250 ml·min^–1), renal clearance (131 to 150 ml·min^–1), mean residence time (10.5 to 11.3 h), half-life (8.8 to 9.4 h), and steady-state volume of distribution (V_ss) (147 to 157 l) indicated that nadolol was extensively distributed and slowly cleared from the body. There was a linear correlation (r ²=0.97) between the area under the plasma concentration of nadolol versus time curve (AUC) and the dose. All pharmacokinetics parameters, except V_ss, were slightly, but significantly, different at the 4 mg dose. Superposition of the dose-normalized average concentrations indicated that despite these minor differences in parameters, the pharmacokinetic behavior of nadolol was linear with respect to dose. Urinary excretion of nadolol was dose independent.     

Pharmacokinetics of primaquine in patients withP. Vivax malaria

Summary The pharmacokinetics of primaquine (PQ) and its major carboxylic acid metabolite (PQC) have been studied in seven Indian patients withP. vivax malaria following PQ 15 mg/day p.o. for 14 days. After a single oral dose on Day 1, a mean peak blood concentration of 50.7 ng/ml PQ was attained after 2.3 h, which declined monoexponentially with a half-life of 5.6 h. The mean total body clearance was 37.6 l/h and the volume of distribution was 2921. The mean renal excretion (0–24 h) of the drug was only 0.54% of the dose and renal clearance was 0.189 l/h. Following chronic administration, none of the pharmacokinetic parameters was affected, and a steady state blood concentration of 2.5–4.2 ng/ml PQ was attained. After the first dose of PQ, PQC had a mean area under the blood concentration — time curve 11-fold higher than that of the parent drug. In contrast to the rapid distribution and elimination of PQ, the metabolite showed a longer mean residence time and accumulation in the body. The mean C_max and AUC of the metabolite on Day 14 were 48 and 40% higher than the corresponding Day 1 values. The metabolite could not be detected in urine at any time in any patient. PQ and its metabolite did not show any accumulation in blood cells.Communication No.797 from Hindustan CIBA-GEIGY Limited, Research Centre     

Preparation and characterization of amoxicillin mucoadhesive microparticles using solution-enhanced dispersion by supercritical CO2

The purpose of this research was to formulate and systemically evaluate in vitro and in vivo performances of mucoadhesive amoxicillin microparticles for the potential use in the treatment of gastric and duodenal ulcers, which were associated with Helicobacter pylori. The chitosan/amoxicillin microparticles were successfully prepared in a process of solution-enhanced dispersion by supercritical CO₂ (SEDS). The morphological characteristics of the mucoadhesive microparticles were studied under scanning electron microscope. The resulted microparticles with mean sizes ranged from 1.0 and 2.5?µm had good mucoadhesive properties. In vitro and in vivo mucoadhesive tests showed that chitosan/amoxicillin mucoadhesive microparticles adhered more strongly to gastric mucous layer and could retain in gastrointestinal tract for an extended period of time. The X-Ray Powder Diffractometry and Differential Scanning Calorimetry analysis demonstrated that the SEDS process was a typical physical coating process to produce drug-polymer composite microparticles, which is favourable for drugs since there is no changes in chemistry. In vitro release test showed that amoxicillin released faster in pH 1.0 hydrochloric acid (HCl) than in pH 7.8 phosphate buffer. In vivo H. pylori clearance tests were also carried out by administering amoxicillin powder and mucoadhesive microparticles to H. pylori infectious Wistar rats under fed conditions at single dose or multiple dose(s) in oral administration. The results showed that amoxicillin mucoadhesive microparticles had a better clearance effect than amoxicillin powder. In conclusion, the prolonged gastrointestinal residence time and enhanced amoxicillin stability resulting from the mucoadhesive microparticles of amoxicillin might make a contribution to H. pylori complete eradication.     

Elimination of phenacetin and phenazone by man before and after treatment with phenobarbital

Summary After the oral administration to volunteers of phenacetin (15 mg/kg) the highest concentration in blood was reached 2 h later. The decline appeared to follow first order kinetics with an apparent biological half-life (t/2) of 0.8 h. The highest concentration in blood of the unconjugated metabolite, paracetamol, was twice that of phenacetin. About 70 per cent of a dose of phenacetin was excreted as conjugated paracetamol in the urine, and 70 per cent of this compound was eliminated during the first 12 h period. — After daily administration of 1.4, 2.5 and 3.6 mg/kg of Phenobarbital, each dose sequentially for 1 week, the apparent biological half-life of phenacetin and the elimination rates of its metabolites, unconjugated and conjugated paracetamol, remained unchanged. The elimination rate of phenazone (16 mg/kg) was increased by 40 per cent in the same subjects after treatment with phenobarbital. — The blood concentration of phenacetin varied more than 20 times between individuals, although no individual variation was found for the blood levels of unconjugated paracetamol.Parts of this paper have been published in a short communication [11] and at the 11. Frühjahrstagung der Deutschen Pharmakologischen Gesellschaft on March 15–18, 1970 [12].