Pharmacokinetics of recombinant human luteinizing hormone after intravenous, intramuscular, and subcutaneous administration in monkeys and comparison with intravenous administration of pituitary human luteinizing hormone.

To assess the pharmacokinetics of recombinant human LH (rhLH) in monkeys, we measured serum LH levels after single iv injection and after single and repeated doses by the im or sc route. A single iv bolus of 400 IU/kg rhLH or pituitary hLH (phLH) in six cynomolgus monkeys resulted in parallel concentration-time curves. The initial and terminal half-lives of rhLH (0.8 and 11 h) were comparable to those of phLH (0.6 and 10 h). The serum levels of phLH were consistently higher due to the fact that the immunological dose of phLH was higher. Administration of increasing iv doses of rhLH (10, 63, and 400 IU/kg) to six monkeys showed that the pharmacokinetics are linear over this dose range. The total clearance for the two higher doses was 0.03 L/h.kg. Systemic bioavailability was 50% after a single sc injection of 400 IU/kg and 61% after a single im injection of the same dose. The peak concentration (180 IU/L) after im injection was reached after 2.7 h. This was higher and sooner than after sc injection (110 IU/L after 5.3 h). The terminal half-life by both routes was similar to that seen after iv injection (11 h). Daily sc or im administration of 63 IU/kg for 7 days confirmed these findings. There was no accumulation of rhLH. Some monkeys developed antibodies, especially after repeated administration. They were excluded from the analysis. No significant local or systemic adverse events occurred.

Pharmacokinetics of flunoxaprofen in rats, dogs, and monkeys.

The kinetics of flunoxaprofen, an anti-inflammatory nonsteroidal drug, was studied in rats (Charles River), dogs (beagles), and monkeys (Macaca fascicularis). Plasma levels, after oral and iv administration of 20-40 mg/kg, and urinary excretion were followed for 24-72 h; the determinations were performed by gas chromatography. Levels in various organs and in rat bile were also determined. The pharmacokinetic parameters show noteworthy similarities in the three species studied: high bioavailability, extensive biotransformations with small urinary excretion of unmodified drug, total clearance between 40 and 50 mL/h/kg, and peak plasma levels of approximately 200 micrograms/mL. Rats show a high value in volume of distribution (2 L/kg), whereas dogs and monkeys show a volume of distribution between 0.13 and 0.18 L/kg. In the rat, the half-life of the drug is approximately 70 h, whereas in the dog and monkey, a half-life of approximately 2 h was found.

Comparative bioavailability of Silipide, a new flavanolignan complex, in rats.

The comparative pharmacokinetics of Silipide (IdB 1016, a silybin-phosphatidylcholine complex) and silybin were investigated by measuring unconjugated and total plasma silybin levels as well as total biliary and urinary silybin excretion in rats following administration of a single oral dose (200 mg/kg as silybin). Mean peak levels of unconjugated and total silybin after IdB 1016 were 8.17 and 74.23 micrograms/ml respectively. Mean AUC (0-6 h) values were 9.78 and 232.15 h.micrograms.ml-1 indicating that about 94% of the plasma silybin is present in a conjugated form. After administration of silybin, plasma levels of both unconjugated and total compound were under the analytical detection limit. Cumulative biliary (0-24 h) and urinary (0-72 h) excretion values after administration of IdB 1016 accounted for 3.73% and 3.26% of the administered dose, respectively. After silybin administration, the biliary and urinary excretion accounted for only 0.001% and 0.032% of the dose respectively. Our results indicate a superior bioavailability of silybin administered orally as IdB 1016. This was due mainly to an impressive increase in gastrointestinal absorption.

Distribution and excretion of teicoplanin in rats after single and repeated intravenous administration.

After the i.v. administration of a single 10 mg/Kg dose of [14C] teicoplanin to rats, no substantial differences were found between males and females as regards the hematic profile, the excretion pattern and tissue distribution. About 74% of the administered radioactivity was recovered in the 0-120 hours interval and more than 90% of this amount was found in the first 24 hours. In the 0-120 hour interval, 7% of the dose was excreted with the faeces, while the total 14C excreted (including the cage washing) was 82% of the dose. A high affinity of [14C] teicoplanin for the kidneys and especially for the cortex area was displayed in the distribution study. Similar findings were observed when 7 intravenous doses (10 mg/Kg each) were given to male rats at 24 hour intervals. The percentage of the total dose found in urine seven days after the last administration remained close to 70% and also the excretion data observed in each collection interval after the last treatment were comparable with those obtained in the single dose study. The distribution in tissues was very similar to that of the single dose experiment. The high 14C concentration level found in the kidneys of animals killed at 5 min after the last treatment was cleared with a disappearance rate comparable with that observed in the single dose experiment.

Linearity of levodropropizine, a new antitussive drug, in the healthy volunteer.

The object of this study was to determine whether the pharmacokinetics of levodropropizine were linear. Twelve healthy adult male volunteers received oral doses use of 30, 60 and 90 mg of levodropropizine. A cross-over design was used. With the exception of Cmax, and AUC the pharmacokinetics of levodropropizine in the dose range studied are similar. The relationship between the doses and AUCs and the statistical comparison of AUCs (Anova test and Westlake test) confirm that in the range 30-90 mg the plasma pharmacokinetics of levodropropizine are linear.

Disposition of premazepam, an anti-anxiety pyrrolodiazepine, in the cynomolgus monkey.

The plasma levels, tissue distribution and the urinary elimination of total radioactivity and of unchanged premazepam were determined in cynomolgus monkeys given intravenously the 14C labelled pyrrolo diazepine. Following the i.v. injection, both total 14C and the unchanged drug disappeared from the central compartment in a biphasic manner with terminal half-lives of 11.9 and 3.7 h respectively. Elimination occurred mainly via the kidneys with 58% of the administered 14C and 16% of premazepam recovered in 48 h. Tissue distribution of radioactivity (whole-body autoradiography) showed as target tissues the emunctory organs and the melanin rich choroid of the eyes and the traiv follicles. Interestingly, five min after the i.v. dose the distribution of premazepam in the brain indicated an homogeneous diffusion in the different areas with a preferential affinity for the grey matter.

Pharmacokinetic study in rats after single intravenous and oral administrations of [14C]-ITF-296.

Pharmacokinetics of [14C]-ITF-296 and its metabolites, ITF-1124 and ITF-1577, were studied in rats after a single intravenous (2.5 mg/kg) and oral (10 mg/kg) administration. Radioactivity was measured by LSC while unchanged drug and its metabolites in plasma were assayed by an HPLC-UV method. The absorption of [14C]-ITF-296 after oral administration is practically complete. Elimination of radioactivity occurs mainly in urine (higher than 80%) and the recovery of the dose (higher than 95%) takes place up to 96 h after both treatments. Both by i.v. and p.o. route the results show that the radioactivity is largely excreted in the bile and reabsorbed in the intestine. The tissue distribution study indicates that there is no accumulation or localization of radioactivity in the major organs or blood and no radioactivity levels are found 96 h after either treatment. In addition, whole body autoradiography confirms the tissue distribution pattern, showing no differences between albino and pigmented rats.

14C-NaVP and 14C-PEV repeated dose study in rat. Pharmacokinetic study in rats after repeated oral administrations of 14C-valproic acid sodium salt and 14C-valproic acid pivaloyl oxymethyl ester.

The absorption, excretion and tissue distribution of radioactivity after repeated oral equimolar doses of 14C-valproic acid sodium salt (NaVP) or 14C-valproic acid pivaloyl oxymethyl ester (PEV) was investigated in male rats treated once a day for 14 consecutive days. The 14th day plasma time-course of radioactivity after PEV administrations was characterised by a slow absorption rate with a delayed peak (tmax 2 h, Cmax 7.52 +/- 1.35 microg eq./ml), followed by a plateau lasting up to 8 h. After NaVP treatment, the main peak of radioactivity was observed 0.5 h after administration (Cmax 8.30 +/- 1.26 microg eq./ml) followed by a secondary peak due to biliary enterohepatic recycling. Starting from 4 h onwards, radioactivity levels after PEV treatment were higher than those after NaVP (AUCtau = 113.3 h.microg eq./ml after PEV vs 71.9 h.microg eq./ml after NaVP), but concentrations declined with similar terminal half-lives (52.8 h for PEV and 49.7 h for NaVP). Radioactivity recovered (0-432 h interval) in urine accounted for 79.3% (PEV) and 56.1% (NaVP) while, in faeces accounted for 9.1% (PEV) and 26.1% (NaVP) of total administered dose (14 days). The difference is attributable to a higher excretion of radioactivity in the bile for NaVP. The missing fraction in the total radioactivity balance is probably excreted in expired air, as observed in single dose studies. Radioactivity excreted in bile (0-8 h interval of the last 14th day) accounted for 5.1% (NaVP) and 0.23% (PEV) of the total administered dose (14 days). A possible explanation of this difference may be a different metabolism pattern for the two compounds. The negligible biliary excretion observed after PEV administration is probably due to an inhibition of the glucuronation of valproic acid (or other metabolites) caused by the pivalic acid. Due to the presence of the enterohepatic recycle, the radioactivity levels in intestine, 0.5 and 2 h after administration, were higher after NaVP administration. According to higher plasma levels, the radioactivity concentrations in liver, kidneys and some fat tissues were found to be slightly higher after PEV administration. At 120 h after the last treatment of both compounds, relevant tissue concentrations were observed in mesenteric lymphnodes, perirenal and brown fat. The tissue-plasma radio activity ratio appeared quite similar for the two compounds.

Pharmacokinetic study in dogs and monkeys after single intravenous and oral administrations of [14C]-ITF-296.

Pharmacokinetics of [14C]-ITF-296 and its metabolites, ITF-1124 and ITF-1577, were studied in dogs and monkeys after a single intravenous (2.5 mg/kg) and oral (10 mg/kg) administration. Radioactivity was measured by LSC while unchanged drug and its metabolites in plasma were assayed by an HPLC-UV method. The absorption of [14C]-ITF-296 after oral administration is practically complete both in dogs and in monkeys. The determination of unchanged drug and its metabolites shows quite a similar profile in dogs and monkeys for ITF-296 and ITF-1124 and a different time-course for ITF-1577. Elimination of radioactivity occurs mainly in urine (namely 70-80%) for both species and the recovery of the dose (higher than 90%) takes place up to 96 h after both treatments.

Determination of selenium in plasma, urine and tissues, of standard diet-fed rats and dogs by ETA-atomic absorption spectroscopy with Zeeman background correction.

The method described was developed to be applied in determination of selenium in biological matrices (plasma, urine and tissues) using ETA-AAS with Zeeman background correction. These matrices were obtained from non-fasting S.D. rats and Beagle dogs of both sexes in order to acquire data on the endogenous levels of selenium in these laboratory animals when fed with standard diets. For tissue digestion, a simple procedure using the strong organic base, Soluene 350, was adopted. Precision assays were carried out monitoring Se(IV) levels in spiked matrices (range from 25 to 200 ng) and obtaining relative standard deviations (RSD%) in the range from 3.2% to 14.5% (intra-day) and from 7.6% to 15.9% (inter-day). Accuracy assays gave relative errors (RE%) in the range from -6.5 to 4.2% (intra-day) and from -5.5% to 5.7% (inter-day). The validity of the method was checked on reference material (NBS SRM 1577 bovine liver) and the values obtained correlated with the certified ones. The detection limit assumed was 0.9 ng/ml, whereas the quantitation limit of selenium in matrices ranged from 2 to 5 ng/ml (or g), depending on the kind of sample.