Pharmacokinetics of methylprednisolone and prednisolone after single and multiple oral administration

The pharmacokinetics of methylprednisolone and prednisolone were evaluated in 24 healthy men after oral administration of single and multiple doses for 3 days. For each drug, 6 different administration regimens with doses ranging from 1 to 80-mg of methylprednisolone and 1.25 to 100-mg of prednisolone, and administration intervals ranging from 3 to 24 hours for both were investigated. Plasma was assayed using a normal phase high-performance liquid chromatography (HPLC) method. Methylprednisolone showed linear pharmacokinetics with no apparent dose or time dependency. Prednisolone showed marked dose dependency with higher clearance and volume of distribution for higher doses. This can be explained by its saturable protein binding of plasma, because unbound clearance and unbound volume of distribution were not dose-dependent. After multiple administration, prednisolone showed significant time-dependent pharmacokinetics with increased unbound clearance and increased unbound volume of distribution. Due to the complicated pharmacokinetic properties of prednisolone, it is extremely difficult to determine the dose needed to obtain a desired target concentration. The pharmacokinetics of methylprednisolone are more predictable because methylprednisolone concentrations are proportional to dose, and no determination of plasma protein binding is needed.     

Pharmacokinetics of mivacurium isomers and their metabolites in healthy volunteers after intravenous bolus administration

BACKGROUND: Previous studies report the pharmacokinetics of mivacurium isomers after an infusion using venous blood sampling. Although the extent of the mivacurium arterial-venous gradient is not known, the sampling site is likely to influence mivacurium pharmacokinetic parameters because the drug is rapidly metabolized as it traverses the circulation. The objectives of this study were (1) to determine the pharmacokinetics of mivacurium isomers in healthy persons after intravenous bolus administration using intensive arterial blood sampling, and (2) to characterize the formation and elimination of mivacurium metabolites in human plasma. METHODS: Eight persons classified as American Society of Anesthesiologists physical status 1 or 2 who were scheduled to undergo elective surgery under balanced anesthesia received 0.15 mg/kg mivacurium chloride as an intravenous bolus. Arterial blood samples were collected every 10 s during the first 2 min and at frequent intervals for 4 h thereafter. Plasma concentrations of mivacurium isomers and their metabolites were determined by two stereoselective high-performance liquid chromatographic methods coupled with fluorometric detection and noncompartmental pharmacokinetic parameters. RESULTS: Mean elimination half-lives of the trans-trans, cis-trans, and cis-cis isomers were 2.4, 2, and 28.5 min, respectively, with corresponding mean plasma clearances of 29.2, 45.7, and 6.7 ml.min 1.kg-1. The volumes of distribution at steady state of the trans-trans, cis-trans, and cis-cis isomers were 0.047, 0.054, and 0.189 l/kg, respectively. Plasma concentrations of monoester and alcohol metabolites peaked 25 s (median) after mivacurium injection, with half-lives in the range of 90 min, except for the cis alcohol metabolite, which was only negligibly and transiently formed. CONCLUSIONS: Substantial hydrolysis of mivacurium isomers by cholinesterases was confirmed by the rapid appearance of mivacurium metabolites in plasma. The intensive arterial sampling proved to be critical for the trans-trans and cis-trans isomers because the area under the curve between 0 and 2 min accounted for 75% and 86% of the total, respectively.     

Pharmacokinetics of enrofloxacin after intravenous, intramuscular and oral administration in houbara bustard (Chlamydotis undulata macqueenii)

The in-vitro activity of enrofloxacin against 117 strains of bacteria isolated from bustards was determined. Minimum inhibitory concentrations for 72% of the Proteus spp., E. coli, Salmonella spp. and Klebsiella spp. (n = 61) and for 48% of the Streptococci spp. and Staphylococci spp. (n = 31) were < or = 0.5 microg/mL. The minimum inhibitory concentration (MIC) of 76% of Pseudomonas spp. (n = 25) was < or = 2 microg/mL. Fourteen strains were resistant to concentrations > or = 128 microg/mL. The elimination half-lives (t1/2 elim beta) (mean +/- SEM) of 10 mg/kg enrofloxacin in eight houbara bustards (Chlamydotis undulata) were 6.80 +/- 0.79, 6.39 +/- 1.49 and 5.63 +/- 0.54 h after oral (p.o.), intramuscular (i.m.) and intravenous (i.v.) administration, respectively. Enrofloxacin was rapidly absorbed from the bustard gastro-intestinal tract and maximum plasma concentrations of 1.84 +/- 0.16 microg/mL were achieved after 0.66 +/- 0.05 h. Maximum plasma concentration after i.m. administration of 10 mg/kg was 2.75 +/- 0.11 microg/mL at 1.72 +/- 0.19 h. Maximum plasma concentration after i.m. administration of 15 mg/kg in two birds was 4.86 microg/mL. Bioavailability was 97.3 +/- 13.7% and 62.7 +/- 11.1% after i.m. and oral administration, respectively. Plasma concentrations of enrofloxacin > or = 0.5 microg/mL were maintained for at least 12 h for all routes at 10 mg/kg and for 24 h after i.m. administration at 15 mg/kg. Plasma enrofloxacin concentrations were monitored during the first 3 days of treatment in five houbara bustards and kori bustards (Ardeotis kori) with bacterial infections receiving a single daily i.m. injection of 10 mg/kg for 3 days. The mean plasma enrofloxacin concentrations in the clinical cases at 27 and 51 h (3.69 and 3.86 microg/mL) and at 48 h (0.70 microg/mL) were significantly higher compared with the 3 h and 24 h time intervals from clinically normal birds. The maximum plasma concentration (Cmax)/MIC ratio was ranked i.v. (10/mg/kg) > i.m. (15 mg/kg) > i.m. (10 mg/kg) > oral (10 mg/kg), but it was only higher than 8:1 for i.v. and i.m. administrations of enrofloxacin at 10 mg/kg and 15 mg/kg, respectively, against a low MIC (0.5 microg/mL). A dosage regimen of 10 mg/kg repeated every 12 h, or 15 mg/kg repeated every 24 h, would be expected to give blood concentrations above 0. 5 microg/mL and hence provide therapeutic response in the bustard against a wide range of bacterial infections.     

Pharmacokinetics of liposome-encapsulated meglumine antimonate after intramuscular and subcutaneous administration in dogs

We describe a transient figurate erythema in an 11-month-old female infant with a 2-month history of arcuate and annular erythematous lesions localized on the face, trunk, and limbs. Constitutional symptoms were absent. Previous medical history was unremarkable. Full blood examination, erythrocyte sedimentation rate, antistreptolysin-O titer, anti-Ro, and anti-La antibodies were within normal limits or negative. Histologic examination revealed a superficial and deep perivascular and interstitial dermatitis constituted mostly of neutrophils and abundant nuclear dust. The lesions resolved spontaneously within a few months without scarring or atrophy. Recurrence has not occurred. This case suggests that figurate erythemas in infants rarely may disclose a neutrophilic histologic pattern, which must be differentiated from that of other neutrophilic dermatoses.     

Pharmacokinetics of gentamicin following single-dose parenteral administration to goats

The disposition kinetics of parenterally administered gentamicin (5 mg kg-1) has been studied in Gaddi goats. The serum concentration-time profile was described by bi-exponential and mono-exponential equations following intravenous (i.v.), intramuscular (i.m.) and subcutaneous (s.c.) administration with elimination half-life values of 0.96 +/- 0.09, 2.37 +/- 0.47 and 3.56 +/- 0.39 h, respectively. The apparent volume of distribution following i.v. administration (Vdarea: 0.26 +/- 0.041 kg-1) reflected limited extracellular distribution of the drug. The bioavailability was higher following i.m. administration (96.3%) compared to s.c. (76.9%). In view of the significantly longer biological half-life and larger area under the curve values, the s.c. route may be preferred. It is concluded that a suitable and practical dosage recommendation for gentamicin in goats would be 3.35 mg kg-1 body weight given s.c. at 12 h intervals.     

Pharmacokinetics of clentiazem after intravenous and oral administration in healthy subjects

This study characterized the pharmacokinetics of clentiazem (CLZ) after a single intravenous bolus (IV) and oral (PO) dose in humans. Twenty-four healthy male subjects (28.5 +/- 5.2 years; 77 +/- 8.2 kg) received IV (20 mg) and PO (80 mg) doses of CLZ as part of a four-way, randomized, complete crossover study. Serial blood samples were drawn up to 48 hours after administration of the drug. Plasma samples were analyzed for CLZ and three metabolites by a high-pressure liquid chromatography method. The values (mean [CV, %]) for systemic clearance, volume of distribution at steady-state, and half-life of CLZ were 63.6 L/hour (23.5), 756.1 L (19.1), and 10.6 hours (33.1), respectively, after IV administration. The peak plasma CLZ concentration (Cmax) and time to Cmax were 37.0 ng/mL (38.7) and 3.7 hours (22.9), respectively, with a lag time after PO administration. The absolute bioavailability of PO CLZ was 45% (30.7). The ratio of area under the curve of N-desmethyl CLZ to that of CLZ increased from 0.15 (57.0) after IV to 0.60 (21.4) after PO administration, suggesting a significant first-pass effect. The mean residence time and mean absorption time of CLZ were 12.3 hours (24.3) and 3.1 hours (88.1), respectively. The plasma concentration-time data of CLZ can be described by either a one- or two-compartment pharmacokinetic model.     

Pharmacokinetics of acetaminophen after intravenous and oral administration to spontaneously hypertensive rats and normotensive Wistar rats

In our previous study, we reported the faster metabolism of intravenously administered furosemide, hence the smaller diuretic effect of furosemide in spontaneously hypertensive rats (SHRs) of 16 weeks of age than in the age-matched normotensive Wistar rats. In present study, in order to evaluate whether there is some alteration of the phase II metabolism including glucuronide and sulfate conjugations in 16-week-old SHRs and the age-matched Wistar rats, the pharmacokinetic parameters of acetaminophen (A), A-sulfate, and A-glucuronide were investigated after intravenous (iv) and oral 100 mg/kg administration of A to 16-week-old SHRs and the age-matched Wistar rats. After iv administration of A, the mean fraction of iv dose excreted in 24-h urine as A-sulfate (75.6 versus 67.8%) and the partial clearance of A to A-sulfate (8.10 versus 6.89 mL/ min/kg) were significantly greater in SHRs than in Wistar rats. Conversely, the mean fraction of iv dose excreted in 24-h urine as A-glucuronide (9.39 versus 15.0%) and the partial clearance of A to A-glucuronide (1.01 versus 1.49 mL/min/kg) were significantly smaller in these SHRs. Similar results were also obtained after oral dosing of A. The in vitro sulfotransferase activity toward A was significantly smaller (0.397 versus 0.331 microg/min/mg of protein) in 16-week-old SHRs than in the age-matched Wistar rats, whereas, the glucuronyltransferase activity toward A was not significantly different between these SHRs and Wistar rats. On the other hand, there was no significant difference in the both sulfotransferase and glucuronyltransferase activity toward A between 6-week-old SHRs and age-matched Wistar rats. Therefore, the alterations in sulfation and perhaps glucuronidation of A between 16 -week-old SHRs and normotensive Wistar rats suggested that some physiological factors derived from the chronic hypertensive status in SHRs might affect the disposition of drugs.     

Pharmacokinetics of terbinafine and five known metabolites in children, after oral administration

BACKGROUND: Deferiprone is an orally active iron-chelating agent that is being evaluated as a treatment for iron overload in thalassemia major. Studies in an animal model showed that prolonged treatment is associated with a decline in the effectiveness of deferiprone and exacerbation of hepatic fibrosis. METHODS: Hepatic iron stores were determined yearly by chemical analysis of liver-biopsy specimens, magnetic susceptometry, or both. Three hepatopathologists who were unaware of the patients' clinical status, the time at which the specimens were obtained, and the iron content of the specimens examined 72 biopsy specimens from 19 patients treated with deferiprone for more than one year. For comparison, 48 liver-biopsy specimens obtained from 20 patients treated with parenteral deferoxamine for more than one year were similarly reviewed. RESULTS: Of the 19 patients treated with deferiprone, 18 had received the drug continuously for a mean (+/-SE) of 4.6+/-0.3 years. At the final analysis, 7 of the 18 had hepatic iron concentrations of at least 80 micromol per gram of liver, wet weight (the value above which there is an increased risk of cardiac disease and early death in patients with thalassemia major). Of 19 patients in whom multiple biopsies were performed over a period of more than one year, 14 could be evaluated for progression of hepatic fibrosis; of the 20 deferoxamine-treated patients, 12 could be evaluated for progression. Five deferiprone-treated patients had progression of fibrosis, as compared with none of those given deferoxamine (P=0.04). By the life-table method, we estimated that the median time to progression of fibrosis was 3.2 years in deferiprone-treated patients. After adjustment for the initial hepatic iron concentration, the estimated odds of progression of fibrosis increased by a factor of 5.8 (95 percent confidence interval, 1.1 to 29.6) with each additional year of deferiprone treatment. CONCLUSIONS: Deferiprone does not adequately control body iron burden in patients with thalassemia and may worsen hepatic fibrosis.     

Pharmacokinetics of morphine-6-glucuronide and its formation from morphine after intravenous administration

PURPOSE: To develop and assess an automated image cytometric method of apoptotic cell classification for use under conditions in which apoptosis is a rare event (e.g. fibroblastoid cell lines or low-dose irradiation). METHOD: Image acquisition software was adapted to gather double-stained cell images from slides prepared using cell fixation and staining methods that emphasized apoptotic morphology. Chinese hamster ovary cells (CHO) were classified individually by discriminant analysis of morphological and nuclear texture features calculated for each image. Discriminant functions were constructed from a manually classified set of over 60000 cell images categorized as 'normal', 'apoptotic', 'cell doublets' or 'debris' and all subsequent cell images collected were classified using these functions. RESULTS: Application of this technique resulted in a 99.8% accuracy in classification of the normal cell population, and 81.7% classification accuracy for apoptotic cells. This method was then applied to study the time course of the apoptotic response of CHO cells following X-irradiation. Following irradiation with 5 Gy no increase above control levels of apoptosis was noted until 18 h post-irradiation, which corresponded with the release of the G2 block as determined by DNA-content analysis. Apoptotic frequency increased to a peak level of 12.1 +/- 4.6% at 42 h post-irradiation. CONCLUSIONS: Automated image cytometry provides an efficient and consistent method of apoptosis measurement. This study represents the first detailed characterization of the time course and the role of cell division in CHO cell apoptosis.     

Formation of oxyadenine metabolites in the rabbit after intravenous administration of adenine

Adenine, 8-oxyadenine, and 2,8-dioxyadenine were analyzed, by Dowex-50 column chromatography, in rabbit urine four hours after IV infusion of the following doses of adenine in mg/kg: 2, 4, 8.75, 17.5, 35, 70, 140 and 210. The average excretion in mole percentage of the dose was: adenine, 11.1; 8-oxyadenine, 6.1; and 2,8-dioxyadenine, 6.2. The percentage of excretion of 8-oxyadenine and of 2,8-dioxyadenine was unrelated to the dose of adenine. At doses of adenine of 35 mg/kg and above more than 80 per cent of the 2,8-dioxyadenine in the urine was in the form of microscopic pale yellow spherical particles. The particulate 2,8-dioxyadenine was found in the kidney in a very small amount at the dose of 70 mg/kg and in much greater quantities at 140 and 210 mg/kg.     

Some pharmacokinetic parameters of doxycycline in east African goats after intramuscular administration of a long-acting formulation

A compartmental and non-compartmental study was carried out on five adult goats following intramuscular administration of doxycycline at 20 mg/kg bodyweight. The concentration of the drug in serum was determined by a microbiological assay employing Bacillus cereus var mycoides (ATCC 11778) as the test organism. The mean serum concentration (Cmax) and the time of maximum concentration (Tmax) were 1.87 micrograms/ml and 0.85 h, respectively. Using compartmental analysis, the plasma concentration-time curve of doxycycline best fitted a three-compartment open model with first-order absorption. A three-phase disposition of doxycycline was found, the terminal elimination half-life being approximately 40 h. The statistical moment theory was mainly used for non-compartmental analysis. The value obtained for the mean residence time (MRT) was 16.4 h. The mean values for the volume of distribution at steady state (Vdss), determined by compartmental and non-compartmental analyses, were 8.73 and 13.19 L/kg, respectively. There were no statistically significant differences when the major pharmacokinetic parameters were compared. It was concluded that the pharmacokinetic behaviour of doxycycline in goats after intramuscular administration is characterized by a three-compartment model with a slow terminal elimination phase. Based on current knowledge, this could be due to enterohepatic recycling and/or flip-flop kinetics. The study indicated that a single intramuscular administration of 20 mg/kg of doxycycline may only provide therapeutic concentrations for up to 24 h owing to slow absorption at the injection site.     

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

Fifteen mycoplasma-free chickens were contact exposed to five chickens that had been experimentally infected with one of three different strains (two field strains and one laboratory strain) of Mycoplasma synoviae (MS). Culture and polymerase chain reaction (PCR) were positive by 3 days postinoculation (PI) in the experimentally infected birds. Lateral transmission was found by 7-14 days postexposure. Positive serum plate agglutination (SPA) results were detected 3-4 wk after positive culture and/or PCR in individual birds. By 42 days PI, all the birds in the groups exposed to field strain K1858 or K3344 had become infected as determined by culture and PCR, whereas only half of the birds in the group exposed to laboratory strain WUV1853 had become infected. Because of the unanticipated lack of seroconversion to hemagglutination inhibition (HI) and enzyme-linked immunosorbent assay (ELISA) in infected chickens, the study was extended. Each group was split into two groups of 10 birds each, one of which was vaccinated with a live B1/LaSota Newcastle disease (ND) vaccine virus to determine if a viral respiratory challenge might incite a stronger antibody response to the mycoplasma infection. All the birds were tested for seroconversion 14 and 21 days later. Of the birds vaccinated for ND, a slightly greater number were MS positive by SPA than the nonvaccinated birds. This effect was not present 21 days after vaccination, and there was no significant difference in the MS HI results from these groups, suggesting that the viral respiratory infection had little direct impact on seroconversion. The virulent field strain (K3344) elicited a stronger MS antibody response than the other strains. All results from the MS ELISA were negative in all groups through 9 wk. Positive results from PCR analysis correlated well with culture results, whereas serologic tests did not detect MS infection for several weeks. Monitoring programs solely dependent on seroconversion may be inadequate for diagnosis and control of mycoplasma infections.     

Pharmacokinetics and pharmacodynamics of recombinant human erythropoietin after single and multiple subcutaneous doses to healthy subjects

OBJECTIVES: To understand the pharmacokinetic and pharmacodynamic properties of recombinant human erythropoietin (epoetin alfa) and to continue to optimize dosing regimens by determining whether administration of single high doses of epoetin alfa is as effective as repeated administration. METHODS: Epoetin alfa was administered as single subcutaneous doses of 300, 450, 600, 900, 1200, 1350, 1800, and 2400 IU/kg and in multiple subcutaneous dose regimens: 150 IU/kg 3 times a week for 4 weeks and 600 IU/kg once per week for 4 weeks in 2 open-label, randomized placebo-controlled studies in healthy volunteers. RESULTS: The absorption rate of epoetin alfa after subcutaneous administration was independent of dose, whereas clearance was dose-dependent in that it decreased with increasing dose. There was a linear relationship between response measured as percentage of reticulocytes area under the curve (AUC) and erythropoietin AUC for single doses up to 1800 IU/kg. Beyond the 1800 IU/kg dose, there was a saturation of response. The mean percentage of reticulocytes after single-dose regimens began to increase by days 3 to 4, reached their maximum at days 8 to 11, and returned to baseline values by day 22. In contrast, the mean percentage of reticulocytes after both multiple-dose regimens were maintained above baseline values through day 22 as both regimens stimulated modest but sustained increases in percentage of reticulocytes (1% to 2%). The mean percentage of reticulocytes AUC for 600 IU/kg epoetin alfa given once a week for 4 weeks was apparently greater than the mean percentage of reticulocytes AUC for 150 IU/kg 3 times a week for 4 weeks. Although daily oral iron supplementation was given, mean serum ferritin levels declined by approximately 75% through day 22 in subjects treated with multiple doses of epoetin alfa. CONCLUSIONS: These findings show that the pharmacologic response to epoetin alfa is a function of dose and dosing regimen. Repeated administration of epoetin alfa was more effective in stimulating a reticulocyte response than single-dose administration of the same total amount of epoetin alfa.     

Pharmacokinetics and metabolic disposition of 14C-metronidazole-derived radioactivity in rat after intravenous and intravaginal administration

Urinary metabolites and the pharmacokinetics of radioactivity derived from 14C-metronidazole (14C-MTZ) were determined after intravenous (iv) or intravaginal (ivg) administration of 10 mg/kg to adult rats. Following iv or ivg administration, the disappearance of 14C from blood followed the kinetics of a two-compartment open-system model. The blood half-lives of 14C during the beta-phase were 10.9 +/- 1.6 and 13.6 +/- 4.2 hr, after iv and ivg administration, respectively. After ivg application, the MTZ-derived radioactivity was detected in tail blood at 5 min, peaked at 1 hr, declined rapidly to 6 hr and more slowly thereafter. The vaginal absorption half-life of 14C-MTZ was 0.28 +/- 0.09 hr. About 12% of the administered dose remained in the vagina after 1 hr and 1.5% after 24 hr. At 24 hr, the tissue distribution and concentration of 14C were similar in iv and ivg dosed rats, the highest 14C concentration being present in the kidneys and lowest in the fat. The percentages of the dose excreted in 24 hr in the urine and feces were 58 and 15 after iv administration, compared to 37 and 40 after the ivg route, respectively. Unchanged 14C-MTZ and five of its metabolites were detected in the urine irrespective of the route of administration. The results show that metronidazole is rapidly absorbed through the vaginal mucosa of the rat and the metabolism and excretion of this chemotherapeutic agent are influenced by the route of administration.     

Pharmacokinetics of lubeluzole (Prosynap) after single intravenous doses in healthy subjects

The single-dose pharmacokinetics of lubeluzole were investigated in 2 single-blind, placebo-controlled, dose-escalation studies in healthy male subjects. In the first study, 6 subjects received an intravenous infusion of 2.5, 5, and 10 mg lubeluzole. In the second study, a 15 mg dose of lubeluzole was administered to 6 subjects, of whom 5 also received 20 mg and 2 also 25 mg lubeluzole. Following the infusion, plasma lubeluzole concentrations decayed biphasically, with a mean distribution half-life (t1/2alpha) of 30 to 65 minutes and a mean terminal half-life (t1/2beta) of 15 to 24 hours. The results of the 2 studies indicate that lubeluzole exhibits linear kinetics over the dose range tested in healthy male subjects.     

Pharmacokinetics of medroxyprogesterone acetate after single and multiple injection of Cyclofem in Chinese women

The intake of fluorides with water, food, dental fluoride preparations, or in particular fluoride supplements, such as NaF tablets, may lead to dental fluorosis. In the present study conducted in a nonfluoridated area in Germany, developmental enamel defects were examined using the Modified Developmental Defects of Enamel Index (Mod DDE Index), which subdivides enamel defects into the categories demarcated (Mod DDE score 1) and diffuse (Mod DDE score 2) opacities and hypoplasia (Mod DDE score 3). 158 children, between 8.5 and 10 years old, were assigned to three examination groups, defined by three different fluoride tablet programs. The children in all three examination groups, F1, F2, and F3, had received 0.25 mg F-/day up to the age of 2 years, F1 and F3 from birth on, F2 beginning with the 7th month of life. F1 and F2 received 0.5 mg F-/day during the 3rd and 0.75 mg F-/day during the 4th and 5th year of life. For F3, beginning with the 3rd year of life, no further recommendations were made. 158 sociodemographically matched children living in a neighboring town served as controls and did not take part in any structured fluoride supplementation program. The proportions of children with Mod DDE scores 1, 2, or 3 at least in one index tooth were significantly higher in the examination groups (40%) than in the control group (20%). Also, the proportions of children with Mod DDE score 2 at least in one index tooth were significantly higher in the examination groups (18%) than in the control group (8%). The proportions of children with Mod DDE score 1 at least in one index tooth were 25% in the examination groups and 17% in the control group. No Mod DDE score 3 was found. Not more than 5% of the children in each group had 50% of their teeth with Mod DDE score 1, 2, or 3. The proportions of teeth per child with Mod DDE score 2 were significantly higher in the examination group than in the control group. While uncontrolled variables cannot be excluded, the observed differences between the experimental and control groups may be attributed to the ingestion of fluoride tablets in the experimental group.     

Pharmacokinetics of phenprobamate after oral administration to healthy subjects

Phenprobamate (CAS 673-31-4) is a centrally acting skeletal-muscle relaxant agent. There are only two studies in the literature about the pharmacokinetics of phenoprobamate in man. The inconsistency between the results of these studies can be attributed partly to the different analytical methodologies used. A sensitive, specific and reproducible HPLC-assay, which may increase the reliability of the pharmacokinetic studies of phenprobamate in plasma, has been developed recently. The objective of this investigation was to assess the single-dose kinetics of phenprobamate in human and to determine the pharmacokinetic parameters of clinical and regulatory concern. The plasma pharmacokinetics of phenprobamate have been investigated following single oral administration at a dose of 800 mg in eleven healthy volunteers.     

Serum and urinary boron levels in rats after single administration of sodium tetraborate

The pharmacokinetics of boron was studied in rats by administering a 1 ml oral dose of sodium tetraborate solution to several groups of rats (n=20) at eleven different dose levels ranging from 0 to 0.4 mg/100 g body weight as boron. Twenty-four-hour urine samples were collected after boron administration. After 24 h the average urinary recovery rate for this element was 99.6+/-7.9. The relationship between boron dose and excretion was linear (r=0.999) with a regression coefficient of 0.954. This result suggests that the oral bioavailability (F) of boron was complete. Another group of rats (n=10) was given a single oral injection of 2 ml of sodium tetraborate solution containing 0.4 mg of boron/100 g body wt. The serum decay of boron was followed and found to be monophasic. The data were interpreted according to a one-compartment open model. The appropriate pharmacokinetic parameters were estimated as follows: absorption half-life, t1/2a=0.608+/-0.432 h; elimination half-life, t1/2=4.64+/-1.19 h; volume of distribution, Vd = 142.0+/-30.2 ml/100 g body wt.; total clearance, Ctot=0.359+/-0.0285 ml/min per 100 g body wt. The maximum boron concentration in serum after administration (Cmax) was 2.13+/-0.270 mg/l, and the time needed to reach this maximum concentration (Tmax) was 1.76+/-0.887 h. Our results suggest that orally administered boric acid is rapidly and completely absorbed from the gastrointestinal tract into the blood stream. Boric acid in the intravascular space does not have a strong affinity to serum proteins, and rapidly diffuses to the extravascular space in proportion to blood flow without massive accumulation or binding in tissues. The main route of boron excretion from the body is via glomerular filtration. It may be inferred that there is partial tubular resorption at low plasma levels. The animal model is proposed as a useful tool to approach the problem of environmental or industrial exposure to boron or in cases of accidental acute boron intoxication.