Urinary pharmacokinetics of 11-nor-9-carboxy-delta9-tetrahydrocannabinol after controlled oral delta9-tetrahydrocannabinol administration

Understanding the pharmacokinetics of orally administered cannabinoids is vitally important for optimizing therapeutic usage and to determine the impact of positive tests on drug detection programs. In this study, gas chromatography-mass spectrometry (limit of quantitation = 2.5 ng/mL) was used to monitor the excretion of total 11-nor-9-carboxy-Delta(9)-tetrahydrocannabinol (THCCOOH) in 4381 urine voids collected from seven participants throughout a controlled clinical study of multiple oral doses of THC. The National Institute on Drug Abuse Institutional Review Board approved the study and each participant provided informed consent. Seven participants received 0, 0.39, 0.47, 7.5, and 14.8 mg THC/day for five days in this double blind, placebo-controlled, randomized protocol conducted on a closed research ward. No significant differences (P /= 15 ng/mL. An average of only 2.9 +/- 1.6%, 2.5 +/- 2.7%, 1.5 +/- 1.4%, and 0.6 +/- 0.5% of the THC in the 0.39, 0.47, 7.5, and 14.8 mg/day doses, respectively, was excreted as THCCOOH in the urine over each 14-day dosing session. This study demonstrated that the terminal urinary elimination t(1/2) of THCCOOH following oral administration was approximately two to three days for doses ranging from 0.39 to 14.8 mg/d. These data also demonstrate that the apparent urinary elimination t(1/2) of THCCOOH prior to reaching a 15 ng/mL concentration is significantly shorter than the terminal urinary elimination t(1/2). These controlled drug administration data should assist in the interpretation of urine cannabinoid results and provide clinicians with valuable information for future pharmacological studies.     

Pharmacokinetics and excretion of gamma-hydroxybutyrate (GHB) in healthy subjects

In Europe and the United States, the recreational use of gamma-hydroxy butyric acid (GHB) at dance clubs and "rave" parties has increased substantially. In addition, GHB is used to assist in the commission of sexual assaults. The aim of this controlled clinical study was to acquire pharmacokinetic profiles, detection times, and excretion rates in human subjects. Eight GHB-na?ve volunteers were administered a single 25-mg/kg body weight oral dose of GHB, and plasma, urine, and oral fluid specimens were analyzed by using gas chromatography-mass spectrometry (GC-MS). Liquid-liquid extraction was performed after acid conversion of GHB to gamma-butyrolactone. Limits of quantitation of 0.1 (oral fluid), 0.2 (urine), and 0.5 microg/mL (plasma) could be achieved in the selected ion monitoring mode. GHB plasma peaks of 39.4 +/- 25.2 microg/mL (mean +/- SEM) occurred 20-45 min after administration. The terminal plasma elimination half-life was 30.4 +/- 2.45 min, the distribution volume 52.7 +/- 15.0 L, and the total clearance 1228 +/- 233 microL/min. In oral fluid, GHB could be detected up to 360 min, with peak concentrations of 203 +/- 92.4 microg/mL in the 10-min samples. In urine, 200 +/- 71.8 and 230 +/- 86.3 microg/mL, were the highest GHB levels measured at 30 and 60 min, respectively. Only 1.2 +/- 0.2% of the dose was excreted, resulting in a detection window of 720 min. Common side-effects were confusion, sleepiness, and dizziness; euphoria and change of vital functions were not observed. GHB is extensively metabolized and rapidly eliminated in urine and oral fluid. Consequently, samples should be collected as soon as possible after ingestion.     

Toxicokinetics of phthalic acid: the common final metabolite of phthalic acid esters in rats

The toxicokinetic profiles of phthalic acid (PA), which is the common final metabolite of phthalic acid esters (PAE), were studied in rats after orally administering doses 20, 100, or 500 mg/kg. Concentrations of PA were determined in serum or urine by high-performance liquid chromatography (HPLC). The plasma concentrations of PA showed a biexponential increase following oral administration of doses ranging from 20 to 500 mg/kg. The terminal elimination half-lives (t1/2) of PA at dosages of 20, 100, or 500 mg/kg were 6.46 +/- 1.13, 5.19 +/- 3.56, and 5.10 +/- 1.10 h, respectively, total clearances (Cl/F) of PA at 20, 100, or 500 mg/kg were 97.43 +/- 4.20, 215.01 +/- 55.42, and 721.07 +/- 51.81 ml/h, and apparent distribution volumes of PA in the steady state (Vz/F) at 20, 100, or 500 mg/kg were 903.28 +/- 125.28, 1419.87 +/- 527.53, and 5264.86 +/- 993.65 ml, respectively. PA was absorbed rapidly after an oral dose of 500 mg/kg with peak concentration (Cmax) in blood (3.5 +/- 0.33 microg/ml) at 30 min postadministration. After oral administration, the dose-normalized area under the curve (AUC) (146.90 +/- 9.33 microg/h/ml) for 500 mg/kg was significantly greater than at 20 mg/kg (44.69 +/- 2.56 microg/h/ml). Urine analysis indicated that 13 +/- 0.45% of the administered PA dose (at 500 mg/kg, p.o.) was recovered unchanged in urine within 24 h. Data concerning the toxicokinetic profiles of PA improve our understanding of the toxicological potential of PAE and may prove useful for risk assessments of multiple phthalates exposure.     

Kinetics and disposition of hexarelin, a peptidic growth hormone secretagogue, in rats.

To document the disposition of hexarelin, a peptidyl growth hormone secretagogue, male Sprague-Dawley rats received a 5-microg/kg bolus i.v. dose or three single s.c. doses of 5, 10, and 50 microg/kg. To assess hexarelin tissue distribution and excretion, rats were given 1 microg/kg of [(3)H]hexarelin (9.4 Ci/mmol). Metabolism of [(3)H]hexarelin was assessed in bile duct-exteriorized rats given 50 microg/kg where radiolabeled hexarelin biliary and urinary excretion was quantified. After its i.v. injection, hexarelin displayed a half-life of 75.9 +/- 9.3 min, a systemic clearance of 7.6 +/- 0.7 ml/min/kg, and a volume of distribution at steady state of 744 +/- 81 ml/kg. After s.c. administration, the area under the curve (477-3826 pmol.min/ml) estimated with increasing doses confirmed the absence of hexarelin accumulation. Clearance/F (12-15 ml/min/kg) and volume of distribution/F (1208-1222 ml/kg) were dose independent. Hexarelin bioavailability given s.c. was 64%. The highest radioactivity levels were detected in the kidney, liver, and duodenum. The pattern of hexarelin excretion was similar after i.v. or s.c. administrations. Total radioactivity in bile, urine, and feces corresponded to 60, 22, and 10% of the dose, respectively. Of the radioactivity excreted in bile and urine, 90 and 71% was unchanged hexarelin, respectively. These results suggest that: 1) the kinetics of hexarelin appear to be first order up to 50 microg/kg; 2) hexarelin is rapidly absorbed after s.c. administration; 3) biliary excretion is the primary route of hexarelin elimination; and 4) the high recovery of unchanged peptide in bile and urine demonstrates hexarelin stability toward proteolytic enzymes.     

Renal excretion profiles of psilocin following oral administration of psilocybin: a controlled study in man

In a clinical study eight volunteers received psilocybin (PY) in psychoactive oral doses of 212+/-25 microg/kg body weight. To investigate the elimination kinetics of psilocin (PI), the first metabolite of PY, urine was collected for 24 h and PI concentrations were determined by high-performance liquid chromatography with column switching and electrochemical detection (HPLC-ECD). Sample workup included protection of the unstable PI with ascorbic acid, freeze-drying, and extraction with methanol. Peak PI concentrations up to 870 microg/l were measured in urine samples from the 2-4 h collection interval. The PI excretion rate in this period was 55.5+/-33.8 microg/h. The limit of quantitation (10 microg/L) was usually reached 24 h after drug administration. Within 24 h, 3.4+/-0.9% of the applied dose of PY was excreted as free PI. Addition of beta-glucuronidase to urine samples and incubation for 5 h at 40 degrees C led to twofold higher PI concentrations, although 18+/-7% of the amount of unconjugated PI was decomposed during incubation. We conclude that in humans PI is partially excreted as PI-O-glucuronide and that enzymatic hydrolysis extends the time of detectability for PI in urine samples.     

Pharmacokinetics of GST-TatdMt,a recombinant fusion protein possessing potent anti-obesity activity,in Mice

This study examined the absorption and pharmacokinetic disposition of 125I-GST-TatdMt, a recombinant Tat protein possessing potent anti-obesity activity, in mice after vascular and extravascular administration. GST-TatdMt was over-expressed in E. coli, purified, and radioiodinated using the IODO-GEN method. 125I-GST-TatdMt was administered to mice by i.v., i.p. and oral administration at doses of 652.7 nCi (102.3 microg). Upon i.v. injection, the average terminal elimination half-life (t1/2,lambdaz), AUC and AUMC were 6.4 h, 318.2 nCixh/mL and 2518 nCixh2/ mL, respectively. The highest radioactivity was observed in lung followed by liver, spleen, heart and kidney. The t1/2lambdaz values obtained from i.v., i.p., and oral administration were comparable from each other (range 5.8-6.4 h). The absolute bioavailability of 125I-GST-TatdMt was 42.8% and 60.5% after p.o. and i.p. administration, respectively. Given the cell-penetrating nature, 125I-GST-TatdMt may be absorbed into the systemic circulation to a relatively high extent after extravascular administration.     

Extremely low bioavailability of magnesium lithospermate B, an active component from Salvia miltiorrhiza, in rat

We assessed the bioavailability of magnesium lithospermate B (MLB), a main polyphenolic component of Salvia miltiorrhiza and a potent antioxidant having various pharmacological activities, to evaluate its action in vivo. The plasma concentrations of lithospermic acid B (LSB) showed a biexponential decrease after intravenous administration of MLB to rats at doses of 4 and 20 mg/kg. The values of area under the concentration-time curve (AUC; 87.8 +/- 10.9 and 1130 +/- 329 microg.min/mL), total body clearance (CL (tot); 55.52 +/- 7.07 and 23.51 +/- 5.98 mL/min/kg), and distribution volume at steady state (V (ss); 7.60 +/- 1.03 and 3.61 +/- 1.16 L/kg) suggested non-linear pharmacokinetics between the two doses. After oral administration of MLB at a high dose of 100 mg/kg, the mean AUC was barely 1.26 +/- 0.36 microg.min/mL. Absolute bioavailability of MLB was calculated to be 0.0002 from the AUC values after both intravenous dosing at 20 mg/kg and oral dosing at 100 mg/kg. The extremely low bioavailability was caused mainly by poor absorption from the rat gastrointestinal tract; about 65 % of the dose was retained in the tract even 4 h after oral administration, and most of the dose was retained even 20 min after infusion in an in situ jejunal loop experiment. Urinary and biliary excretion of LSB were only 0.70 % +/- 0.26 % and 5.10 % +/- 2.36 %, respectively, over a 30 h time period after intravenous injection despite the large CL (tot) and V (ss) values, and were much less (0.010 % +/- 0.001 % and 0.12 % +/- 0.04 %) after oral dosing. These findings suggest that extensive metabolism, including a first-pass effect, and wide distribution of LSB besides the poor absorption contributed significantly to the extremely low systemic bioavailability.     

Absence of mutagenic activity and a short-term toxicity study of beet pigments as food colorants

Beet colorant was tested for mutagenic activity in five S. typhimurium strains. The absence of mutagenic activity was found with or without S-9 rat liver fractions.Groups of six rats were fed red beet colorant preparations containing 2,000 ppm betalains in the diet for 7 days. No significant differences were noted in body weight gains, feed consumption, or gross pathological alterations compared to the controls.These preliminary toxicological results indicate the potential usage of betalain pigments as a food colorant, but further long term investigations are warranted.     

Identification and characterization of methylated and ring-fission metabolites of tea catechins formed in humans,mice, and rats

(-)-Epigallocatechin gallate (EGCG), the most abundant tea catechin, has been proposed to be beneficial to human health based on its strong antioxidative and other biological activities in vitro. Inadequate knowledge regarding the bioavailability and biotransformation of EGCG in humans, however, has limited our understanding of its possible beneficial health effects. In this study, 4',4' '-di-O-methyl-EGCG (4',4' '-DiMeEGCG) was detected in human plasma and urine by LC/MS/MS following green tea ingestion. Both 4',4' '-DiMeEGCG and EGCG reached peak plasma values (20.5 +/- 7.7 and 145.4 +/- 31.6 nM, respectively, in 4 subjects) at 2 h after the dose. The half-lives of 4',4' '-DiMeEGCG and EGCG were 4.1 +/- 0.8 and 2.7 +/- 0.9 h, respectively. The cumulative urinary excretion of 4',4' '-DiMeEGCG during a 24 h period was 140.3 +/- 48.6 microg, about 5-fold higher than that of EGCG, but the excreted 4',4' '-DiMeEGCG and EGCG in urine only accounted for about 0.1% of ingested EGCG. (-)-5-(3',4',5'-Trihydroxyphenyl)-gamma-valerolactone (M4) and (-)-5-(3',4'-dihydroxyphenyl)-gamma-valerolactone (M6), along with another possible ring-fission metabolite, (-)-5-(3',5'-dihydroxyphenyl)-gamma-valerolactone (M6'), were detected in human urine after green tea ingestion. The cumulative excretion of M4, M6', and M6 during a 24 h period ranged from 75 microg to 1.2 mg, 0.6 to 6 mg, and 0.6 to 10 mg, respectively. The combined excretion of all three ring-fission metabolites accounted for 1.5-16% of ingested catechins. M4, M6', and M6 were all observed after the ingestion of pure EGCG or EGC by human subjects, whereas only M6 was produced after EC ingestion. These metabolites as well as monomethylated EGCG were detected in mice and rats after tea or EGCG administration, and the tissue levels reflected the rather low bioavailability of EGCG in rats. The presently characterized methylated EGCG metabolites and ring-fission products exist in substantial quantities and may contribute to the biological activities of tea.     

Acute, subacute and subchronic safety assessment of betalains rich Rivina humilis L. berry juice in rats

Rivina humilis L. (Phytolaccaceae) accumulates vacuolar pigments betalains. These pigments are synthesized by plants of 11 families in the order caryophyllales. Red beet is the only industrial source of these hydrophilic and low acidic pigments. Betalains rich R. humilis berry juice (RBJ) could be used as alternative source of these pigments. However, there is no information on safety of these berries. In this research work, RBJ was fed to adult (single-dose: 1, 2 and 5 g RBJ/kg bw) and growing (repeated-dosing: 2.5 and 5 g RBJ/kg bw for 35 days; dietary feeding: 0.5%, 1% and 2% RBJ in diet, w/w for 90 days) male rats to assess acute, subacute and subchronic toxic responses. In all the three studies, RBJ was well tolerated plus the feed intake, body and organ weights of RBJ administered groups were comparable to that of untreated control rats. Data on hematology, histology of vital organs, biochemical measurements in serum and liver of RBJ treated rats were comparable to that of control in repeated-dosing and subchronic dietary study. These results suggest that intake of RBJ does not affect growth and normal biochemical homeostasis. Hence, RBJ is safe to consume without any adverse effects in the body.     

Biomarker of pyrethrum exposure

Pyrethrum as well as synthetic pyrethroids like allethrin, resmethrin, phenothrin, tetramethrin, cyfluthrin, cypermethrin, deltamethrin or permethrin are among the insecticides most often used worldwide. With a sensitive and valid gas-chromatographic-high resolution mass spectrometric method, it is possible to detect all pyrethrum and pyrethroid metabolites in one analytical run. Thus, for the first time a background level of trans-chrysanthemumdicarboxylic acid (CDCA) in urine (95th percentile: 0.15 microg/l) as a characteristic, e.g. for a pyrethrum exposure was found. Following a pyrethrum exposure lasting 1 day, CDCA was found in 27 out of 30 subjects with concentrations going up to 54 microg/l urine (mean: 1.1+/-4.4 microg/l). To obtain information about the elimination kinetics of pyrethrum in humans, urinary excretion of CDCA was investigated in three volunteers after oral intake of 0.3mg pyrethrin I. CDCA was detected during the first 36 h after intake with elimination being most rapid during the first 4h (mean elimination half-life: 4.2h).     

Pharmacokinetics of morphine and its surrogates. III: Morphine and morphine 3-monoglucuronide pharmacokinetics in the dog as a function of dose.

The pharmacokinetics of morphine and its derived metabolite, morphine 3-monoglucuronide, were studied in normal and bile-cannulated dogs. High doses (7.2-7.7 mg/kg iv) caused renal and biliary shutdowns and time lags in urinary drug and metabolite excretion and in biliary secretion of the hepatically formed conjugate. Intermediate doses (0.41-0.47 mg/kg iv) inhibited urine flow but not renal clearance. Low doses (0.019-0.07 mg/kg iv) had no apparent effect. Dose-related effects on the total, metabolic, and biliary clearances imply saturable enzymes and/or dose-inhibited hepatic flows, accounting for the major elimination half-lives of 83 +/- 8 and 37 +/- 13 min at the high and low doses, respectively. The slow terminal phase in plasma morphine and metabolite elimination and urinary accumulation is due apparently to the enterohepatic metabolite recirculation after biliary excretion, gastrointestinal hydrolysis, and hepatic first-pass reconjugation. Bile-cannulated dogs showed no fecal drug and no slow terminal plasma and urine elimination phases. Intravenous morphine 3-monoglucuronide was eliminated only renally and showed neither biliary excretion nor prolonged hepatically formed glucuronide elimination. Hepatic morphine clearances at normal therapeutic doses parallel hepatic blood flow and explain the lack of oral morphine bioavailability by anticipating complete first-pass liver metabolism. Renal morphine and morphine conjugate clearances were 85 (+/- 9 SEM) and 41 (+/- 4 SEM) ml/min, respectively, indicating glomerular filtration for the latter and glomerular filtration plus tubular secretion for the former. Urinary morphine and morphine conjugate excretion accounted for approximately to 83% of the dose. Biliary secretion accounted for 11-14% of the dose. Morphine showed dose-independent plasma protein binding of 36 (+/- 1 SEM) % and a red cell-plasma water partition coefficient of 1.11 +/- 0.04 SD. New equations were developed to model the discontinuous morphine and morphine metabolite pharmacokinetics.     

Urinary pharmacokinetics of methamphetamine and its metabolite, amphetamine following controlled oral administration to humans

Methamphetamine is widely abused for its euphoric effects. Our objectives were to characterize the urinary pharmacokinetics of methamphetamine and amphetamine after controlled methamphetamine administration to humans and to improve the interpretation of urine drug test results. Participants (n = 8) received 4 daily 10-mg (low) oral doses of sustained-release (d)-methamphetamine hydrochloride within 7 days. After 4 weeks, 5 participants received 4 daily 20-mg (high) oral doses. All urine specimens were collected during the study. Methamphetamine and amphetamine were measured by GC-MS/PCI. Maximum excretion rates ranged from 403 to 4919 microg/h for methamphetamine and 59 to 735 microg/h for amphetamine with no relationship between dose and excretion rate. The mean molar percentage of dose in the urine as total methamphetamine and amphetamine were 57.5 +/- 21.7% (low dose) and 40.9 +/- 8.5% (high dose). Mean urinary terminal elimination half-lives across doses were 23.6 +/- 6.6 hours for methamphetamine and 20.7 +/- 7.3 hours for amphetamine. Methamphetamine renal clearance across doses was 175 +/- 102 mL/min. The mean amphetamine/methamphetamine percentage ratio based on the area under the urinary excretion-time curve increased over time from 13.4 +/- 6.5% to 35.7 +/- 26.6%. Slow urinary excretion results in drug accumulation and increases in detection time windows. Our findings also support the presence of an active renal excretion mechanism for methamphetamine.     

Pharmacokinetics of the sequential metabolites of loteprednol etabonate in rats

Pharmacokinetics, metabolism and excretion of two sequential inactive metabolites of the soft corticosteroid loteprednol etabonate (LE), Delta1-cortienic acid etabonate (AE) and Delta1-cortienic acid (A), have been investigated in rats. Pharmacokinetic studies (two-compartment model, 10 mg kg(-1) intra-venous bolus of AE or A) found the elimination of both AE (t(1/2)(beta), 12.46 +/- 1.18 min; CL total, 101.94 +/- 5.80 mL min(-1) kg(-1); and K el, 0.24 +/- 0.02 min(-1)) and A (t(1/2)(beta), 14.62 +/- 0.46 min; CL total, 53.80 +/- 1.40 mL min(-1) kg(-1); and K el, 0.18 +/- 0.02 min(-1)) to be significantly faster than that previously determined for the parent LE (t(1/2)(beta), 43.41 +/- 7.58 min; CL total, 67.40 +/- 11.60 mL min(-1) kg(-1); and K el, 0.071 +/- 0.024 min(-1)). For metabolism and excretion evaluations, 1 and 10 mg kg(-1) of either AE or A were intravenously administered, and the urine and bile were collected. AE and A rapidly reached their peak concentrations in the bile and urine, and most of them were eliminated within one hour. Total cumulative excretions at 4 h after 1 and 10 mg kg(-1) injections were 85.51 +/- 3.38% and 67.50 +/- 2.67% for AE, and 71.90 +/- 3.72% and 37.73 +/- 2.69% for A in bile; and 4.84 +/- 1.87% and 13.85 +/- 3.27% for AE, and 24.28 +/- 8.44% and 22.35 +/- 1.12% for A in urine, respectively. After AE administration, the excretion of AE was > 90%, and A was < 10% in all cases, indicating that the elimination of AE was much faster than its metabolism (to A). In a manner similar to that seen for LE, dose-dependent elimination was observed both in AE and A. These results suggested that both AE and A were ideal leads for the design of soft steroids based on the inactive metabolite approach.     

Relative bioavailability of sodium cromoglycate to the lung following inhalation, using urinary excretion

AIMS: To determine if a urinary excretion method, previously described for salbutamol, could also indicate the relative bioavailability of sodium cromoglycate to the lung following inhalation from a metered dose inhaler. Method Inhaled (INH), inhaled+oral charcoal (INHC), oral (ORAL) and oral+oral charcoal (ORALC) 20 mg doses of sodium cromoglycate were given via a randomised cross-over design to 11 healthy volunteers trained on how to use a metered dose inhaler. Urine samples were collected at 0.0, 0.5, 1.0 and up to 24 h post dosing and the sodium cromoglycate urinary concentration was measured using a high performance liquid chromatographic method. RESULTS: No sodium cromoglycate was detected in the urine up to 24 h following ORALC dosing. A mean (s.d.) of 3.6 (4.3) microg, 10.4 (10.9) microg and 83.7 (71.1) microg of the ORAL dose was excreted, in the urine, during the 0.5, 1.0 and 24 h post dose collection periods, respectively. Following INH dosing, the renal excretion was significantly higher (P<0.01) with 32.9 (14.5) microg, 61.2 (28.3) microg and 305.6 (82.3) microg excreted, respectively. The SCG excreted at 0.5, 1.0 and 24 h collection periods following INHC dosing were 26.3 (8.4) microg, 49.3 (18.1) microg and 184.9 (98.4) microg, respectively. There was no significant difference between the excretion rate of sodium cromoglycate following INHC when compared with INH dosing in the first 0.5 and 1.0 h. CONCLUSIONS: The urinary excretion of sodium cromoglycate in the first 0.5 h post inhalation can be used to compare the relative lung deposition of two inhaled products or of the same product using different inhalation techniques. This represents the relative bioavailability of sodium cromoglycate to the lung following inhalation. Similar 24 h urinary excretion of sodium cromoglycate can be use to compare the total dose delivered to the body from two different inhalation products/inhalation methods. This represents the relative bioavailability of sodium cromoglycate to the body following inhalation. Because of the lack of difference between the INH and INHC in the first 0.5 h, the use of activated charcoal is not necessary when this method is used to compare the relative lung bioavailability of different products or techniques.     

Pharmacokinetics of iohexol, a new nonionic radiocontrast agent, in humans

Sixteen healthy men received iohexol intravenously at a concentration of 346 mg of iodine/mL. Doses of 500, 750, 1000, and 1500 mg of iodine/kg of body weight were administered to four volunteers each. Neither clearance nor percent of dose excreted in the urine showed any significant correlation with size of the dose. The overall mean (+/- SD) renal and total body clearances were 120 +/- 18.6 and 131 +/- 18.6 mL/min, respectively. The overall mean apparent volume of distribution was 165 (+/- 30.7) mL/kg. Urine contained 92.3 +/- 4.4% of the dose. Most of the drug (89.9%) was excreted within the first 12 h. An open three-compartment body model gave the best fit to the experimental data. The mean apparent first-order terminal elimination (gamma-phase) half-life was 12.6 h.     

Disposition of hexobarbitone in healthy man: kinetics of parent drug and metabolites following oral administration.

1 Hexobarbitone plasma kinetics were determined in six healthy volunteers, who received 500 mg hexobarbitone orally. In addition urinary excretion rate and cumulative excretion were measured of its three major metabolites: 3'-hydroxyhexobarbitone, 3'-ketohexobarbitone and 1,5-dimethylbarbituric acid. 2 The mean plasma elimination half-life of hexobarbitone was 3.7 +/- 0.9 h (n = 6). Assuming complete absorption, the volume of distribution and the metabolic clearance were 81.3 +/- 20.5 1 and 16.4 +/- 2.9 1/h, respectively. The mean maximal plasma concentration was 7.1 +/- 2.1 micrograms/ml and was reached 1.2 +/- 0.4 h after drug administration. 3 3'-Hydroxyhexobarbitone and 3'-ketohexobarbitone, which are products of allylic side-chain oxidation of hexobarbitone, were excreted in 24 h to the extent of 4.7 +/- 1.3 and 32.1 +/- 11.9% of the dose, respectively. In the same period, 1,5-dimethylbarbituric acid, which is the end product of the epoxide-diol pathway, was excreted to 18.0 +/- 7.8% of the dose. The ratio of the sum of 3'-hydroxy- and 3'-ketohexobarbitone vs 1,5-dimethylbarbituric acid excreted varied with time and amounted ultimately in 24 h urine to 2.3 +/- 1.0. 4 The half-lives of 3'-hydroxyhexobarbitone and 1,5-dimethylbarbituric acid, calculated from their renal excretion rate curves, amounted 5.2 +/- 0.9 and 6.6 +/- 1.3 h and were significantly longer than the half-life of hexobarbitone in plasma. The half-life of 3'-ketohexobarbitone was 4.2 +/- 0.8 h. The maximum excretion rate of 1,5-dimethylbarbituric acid was reached at 7.7 +/- 1.0 h after administration of hexobarbitone. 3'-Hydroxy- and 3'-ketohexobarbitone were excreted with a maximal rate at 2.2 +/- 0.8 and 2.8 +/- 0.4 h respectively.     

Bioavailability and tissular distribution of docetaxel, a P-glycoprotein substrate, are modified by interferon-alpha in rats

Interferon-alpha (IFN-alpha) inhibits intestinal P-glycoprotein (P-gp) expression in rats. In the present study, the effects of repeated pre-treatment with recombinant human INF-alpha (rhIFN-alpha) on oral and intravenous pharmacokinetics of a P-gp substrate, docetaxel (DTX; Taxotere) were investigated in a rat model. The bioavailability and distribution in different organs were also studied. Sprague-Dawley rats were subcutaneously pre-treated with either rhIFN-alpha for 8 days (4MIU kg(-1), once daily) or with pegylated-IFN-alpha (ViraferonPeg; 60 microg kg(-1), Days 1, 4 and 7). The rats were then distributed into sub-groups (n = 5-6) according to the pre-treatment type, and received one dose of [(14)C]DTX (20 mgkg(-1)) either orally or intravenously. Pharmacokinetics studies were then performed over 240 min, at the end of which tissues (intestine, liver, kidneys, lung, heart and brain) were immediately removed for radioactivity quantitation. Non-pegylated and pegylated IFN-alpha both increased DTX oral bioavailability parameters: C(max) (17.0+/-4.0 microg L(-1) (P < 0.02) and 18+/-5.5 microg L(-1) (P < 0.05), respectively, vs 7.4+/-2.5 microg L(-1) for the control) and AUC (0.036+/-0.010 microg h mL(-1) (P < 0.01) and 0.033+/-0.009 microg h mL(-1) (P < 0.01), respectively, versus 0.012+/-0.004 microg h mL(-1) for the control). IFN-alpha also delayed DTX absorption from 60 min in controls to about 95 min and 80 min in non-pegylated and pegylated treated animals, respectively. However, IFN-alpha did not affect intravenous DTX pharmacokinetics and it had a limited effect on tissue distribution at 240 min. [(14)C]DTX was decreased in intestine and enhanced in brain in both pre-treated groups. rhIFN-alpha modified the P-gp-dependent pharmacokinetics of DTX, limited its intestinal efflux and markedly enhanced its oral bioavailability.     

Pentachlorophenol toxicokinetics after intravenous and oral administration to rat.

1. The toxicokinetics of pentachlorophenol (PCP) were studied in rats. Doses of 2.5 mg/kg were given i.v. (bolus, five rats) and orally (gastric intubation, five rats). Concentrations in plasma, urine and faeces were measured by capillary g.l.c. with electron-capture detection. 2. After i.v. administration, the clearance and volume of distribution at steady state were 0.026 +/- 0.003 l/h per kg and 0.25 +/- 0.02 l/kg, respectively. These two parameters exhibit low inter-rat variability (coefficients of variation less than 15%). The half-life of the initial decline of PCP plasma concn. was less than 1.3 h, while the second phase half-life was 7.11 +/- 0.87 h. 3. After oral administration the peak plasma concn. (7.3 +/- 2.8 micrograms/ml) occurred between 1.5 and 2 h and absorption was complete (bioavailability = 0.91-0.97). No distinct distribution phase was observed and the elimination half-life was 7.54 +/- 0.44 h. 4. PCP clearance is essentially metabolic since only 5.3 +/- 0.2% dose is eliminated unchanged by the kidney. About 60% dose was recovered in urine, mainly as conjugated PCP and conjugated tetrachlorohydroquinone (TCHQ). 5. For both routes of administration, about 10% dose was recovered in faeces as PCP and/or metabolites, which indicates that biliary excretion contributes to total elimination.