Slower Elimination Phase Research Articles

S4/L2 - Recent discoveries in pharmacokinetics of drugs of abuse

Tertiary butyl alcohol (TBA) is a small aliphatic alcohol with multiple industrial and scientific uses. A comprehensive pharmacokinetic profile for TBA has not been determined in rats. The purpose of this study was to fully characterize the pharmacokinetics of TBA in male and female F-344 rats following intravenous administration of 37.5, 75, 150 and 300 mg/kg TBA. TBA was observed to undergo a rapid distribution phase followed by a slower elimination phase. The steady-state volume of distribution for TBA was roughly 4.5 times greater than total body water, and the clearance was lower than the estimated glomerular filtration rate. The elimination of TBA appears to saturate at higher closes, as evidenced by a disproportional increase in area under the concentration-time curve and decreased rate of clearance.

Pharmacokinetics of flumequine in sheep after intravenous and intramuscular administration: bioavailability and tissue residue studies.

The pharmacokinetic properties of flumequine and its metabolite 7-hydroxyflumequine were determined in six healthy sheep after single intramuscular (i.m.) and intravenous (i.v) injections at a dose of 6 mg/kg body weight. The tissue residues were determined in 20 healthy sheep after repeated i.m. administration with a first dose of 12 mg/kg and nine doses of 6 mg/kg. The flumequine formulation used was Flumiquil 3% Suspension Injectable. The mean plasma concentrations of flumequine after i.v. administration were described by a three-compartment open model with a rapid distribution and a relatively slow elimination phase. The low value of volume of distribution at steady state (Vdss) (0.52 +/- 0.24 L/kg) and high value of volume of distribution (Vdlambda3) (5.05 +/- 3.47 L/kg) emphasized the existence of a small compartment with a slow rate of return to the central compartment. The mean elimination half-life was 11.5 h. The 7-hydroxyflumequine plasma levels represented 2.3% of the total area under the curve. The mean plasma concentrations of flumequine after i.m. administration were characteristic of a two-compartment model with a first order absorption. The mean maximal plasma concentration (1.83 +/- 1.15 microg/mL) was obtained rapidly, i.e. 1.39 +/- 0.71 h after the i.m. administration. The fraction of dose absorbed from the injection site was 85.00 +/- 30.13%. The minimal concentrations of flumequine during repeated treatment were significantly lower in females than in males. Eighteen hours after the last repeated i.m. administration, the highest concentration of flumequine was observed at the injection sites followed by kidney, liver, muscle and fat. The highest concentration of 7-hydroxyflumequine was observed in the kidney and was ten times lower than the flumequine concentration. The longest flumequine elimination half-life was observed in the fat.

Pharmacokinetics of tertiary butyl alcohol in male and female Fischer 344 rats

Tertiary butyl alcohol (TBA) is a small aliphatic alcohol with multiple industrial and scientific uses. A comprehensive pharmacokinetic profile for TBA has not been determined in rats. The purpose of this study was to fully characterize the pharmacokinetics of TBA in male and female F-344 rats following intravenous administration of 37.5, 75, 150 and 300 mg/kg TBA. TBA was observed to undergo a rapid distribution phase followed by a slower elimination phase. The steady-state volume of distribution for TBA was roughly 4.5 times greater than total body water, and the clearance was lower than the estimated glomerular filtration rate. The elimination of TBA appears to saturate at higher closes, as evidenced by a disproportional increase in area under the concentration-time curve and decreased rate of clearance.

Pharmacokinetic evaluation of enrofloxacin in chickens

1. The pharmacokinetics and bioavailability of enrofloxacin in chickens were investigated following intravenous, intramuscular, subuctaneous and oral administration of 10 mg/kg body weight. A rapid distribution phase was followed by a slower elimination phase. 2. The apparent volume of distribution was 2.2 1/kg. Absorption half lives were 0.37, 0.36 and 0.92 h; elimination half lives were 4.06, 4.48 and 4.29 h and bioavailabilities were 87.5%, 80.8% and 59.6% after intramuscular, subcutaneous and oral administration, respectively. The drug completely disappeared from all tissues after 3 days following oral administration. 3. Based on the bioavailability and disposition kinetics of enrofloxacin, administration of one dose per day should both be practical and adequate to maintain plasma enrofloxacin concentrations within the pharmacologically active but lower than tolerance limit.

Measurement and pharmacokinetic analysis of buspirone by means of brain microdialysis coupled to high-performance liquid chromatography with electrochemical detection

The feasibility of an electrochemical detection system with on-line microdialysis coupled with sensitive microbore high-performance liquid chromatography for the measurement and brain pharmacokinetic analysis of buspirone was investigated. A microdialysis probe was inserted into the right striatum of male Sprague-Dawley rats, which had been administered buspirone (10 mg/kg, i.v.). Dialysates were automatically injected through an on-line injector into a cyano microbore column coupled to an electrochemical detector. Samples were eluted with a mobile phase containing 0.1 M monosodium dihydrogenphosphate-acetonitrile-diethylamine (85:15:0.1, v/v/v, pH 3.0, adjusted with orthophosphoric acid) at a flow-rate of 0.06 ml/min. A biphasic phenomenon with a rapid distribution phase followed by a slower elimination phase was observed from the brain buspirone concentration-time curve. The results indicate that the brain pharmacokinetics of buspirone appear to conform to a two-compartment model.

Fatty Acid Ethyl Esters in the Blood as Markers for Ethanol Intake

To determine the clinical utility of fatty acid ethyl esters (FAEEs) in the blood as a short-term confirmatory marker for ethanol intake and a longer-term marker for ethanol intake after ethanol is no longer detectable. Single-center controlled clinical trial and a blinded comparison involving 48 blood samples that were positive, negative, or equivocal for blood ethanol. Seven healthy subjects (4 men and 3 women, aged 21 to 23 years) participated in the clinical trial. Blood samples from participants for the blinded comparison portion of the study were numbered from 1 to 48 and not identified by name. The 7 healthy subjects ingested a known amount of ethanol at a fixed rate. The concentration of FAEEs in the blood after ethanol intake was determined for a period of up to 24 hours. There was no intervention in the blinded comparison study. In the clinical trial, a pharmacokinetic analysis of FAEE concentration in the blood after ethanol intake was completed for 7 individuals whose blood ethanol level was elevated from 25 to 35 mmol/L. In the blinded comparison, the 48 blood samples that were positive, negative, or equivocal for blood ethanol were analyzed for FAEE concentration. In the clinical trial, the disappearance of FAEEs from the blood followed a decay curve that initially resembled the decay curve for blood ethanol. However, because of a very slow secondary elimination phase, the FAEEs were found to persist in the blood for at least 24 hours after ethanol intake was completed. In the blinded comparison, all 20 samples that were positive for ethanol were positive for FAEEs, 7 of 7 samples equivocal for ethanol were positive for FAEEs, and 21 of 21 negative samples for ethanol were negative for FAEEs. Serum concentration of FAEEs can serve as an excellent short-term confirmatory test for ethanol intake as well as a longer-term marker of ethanol ingestion. Measurement of FAEEs in the blood may be a more sensitive indicator of ethanol ingestion than the measurement of blood ethanol .

Effects of chronic renal failure on plasma clearance of insulin-like growth factor I, des-(1-3)IGF-I, and LR3IGF-I.

Using a rat model of chronic renal failure (CRF), we examined insulin-like growth factor I (IGF-I) clearance, degradation, organ distribution, and IGF binding profiles in plasma. The effects of IGF-binding proteins (IGFBP) on IGF clearance and degradation in CRF were studied using the IGF-I analogues des-(1-3)IGF-I and LR3IGF-I, which bind poorly to IGFBP. Although total clearance of IGF-I was not significantly altered in CRF, half-life and area under the curve were increased in the rapid distribution phase and were reduced in the slow elimination phase. Total clearance of LR3IGF-I was significantly increased. Reduced binding of IGF-I in the 150-kDa complex and increased binding to smaller-molecular-weight IGFBP were observed in CRF. Increased degradation of both IGF-I and LR3IGF-I was associated with reduced IGF binding in the 150-kDa complex. The results suggest that the accumulation of lower-molecular-weight IGFBP with reduced IGF binding in the 150-kDa complex, associated with increased degradation of peptide, may explain, at least in part, the reduced bioactivity of IGF-I observed in CRF.

Determination of Scoparone in Rat Plasma by Liquid Chromatography and Its Application to Pharmacokinetics

Abstract A simple liquid chromatographic method was developed to study the pharmacokinetics of scoparone in the rat plasma. After addition of an internal standard (ferulic acid), plasma was deproteinized by acetonitrile for sample clean-up. The drugs were separated on a reverse phase column and detected by UV detection at a wavelength 340 nm. Acetonitrile-water (30:70, v/v, pH 2.5 adjusted by orthophosphoric acid) was used as a mobile phase. It was applied to the pharmacokinetic study of scoparone in rats after a dose of 5 mg kg−1 intravenous administration. A biphasic phenomenon with a rapid distribution followed by a slower elimination phase was observed from the plasma concentration-time curve.

Pharmacokinetics of enrofloxacin and its metabolite ciprofloxacin after intravenous and intramuscular administrations in sheep

Abstract Objective To evaluate the pharmacokinetics of enrofloxacin and its metabolite ciprofloxacin after administrations of enrofloxacin in sheep. Design Crossover study performed by IV and IM administrations of 2.5 mg of enrofloxacin/kg of body weight to 2 groups of 3 sheep. After a 15-day resting period, the drug administration was repeated, using the alternative route. Animals 6 clinically normal Massese sheep of either sex. Procedure Blood samples were collected at suitable intervals over a 24-hour period, and plasma concentrations of enrofloxacin and its main metabolite ciprofloxacin were determined by a high-performance liquid chromatography method. Pharmacokinetic variables for both substances after IV and IM enrofloxacin administrations were calculated by use of statistical moments and were analyzed, using a crossover ANOVA. Results After IV administration of enrofloxacin, a rapid distribution phase was followed by a slower elimination phase. When the same dose was administered IM, enrofloxacin was rapidly and almost completely absorbed, with bioavailability of 85%. After 24 hours, the mean plasma concentration of ciprofloxacin was similar to that of the parent drug. Conclusions The large volume of distribution indicates that enrofloxacin is widely distributed in the body of sheep. The fraction of enrofloxacin metabolized to ciprofloxacin (35 and 55% for IV and IM administrations, respectively) suggests that, in this species, the antimicrobial activity of enrofloxacin could be attributable, at least in part, to its mam metabolite ciprofloxacin. Clinical Relevance IV or IM administration of 2.5 mg of enrofloxacin/kg provides plasma concentrations higher than mean inhibitory concentration for most pathogens in sheep. (Am J Vet Res 1996;57:1040–1043)

Determination of dicentrine in rat plasma by high-performance liquid chromatography and its application to pharmacokinetics

A simple high-performance liquid chromatographic method was developed to study the pharmacokinetics of dicentrine in rat plasma after 10 mg/kg intravenous administration. After addition of an internal standard (coumarin), plasma was deproteinized by acetonitrile for sample clean-up. The drugs were separated on a reversed-phase Nucleosil C 18 column (250 × 4 mm I.D., particle size 5 μm) and detected by photodiode-array detection at a wavelength of 308 nm. Acetonitrile-water (35:65, v/v, pH 2.5–2.8, adjusted with orthophosphoric acid) was used as the mobile phase. A biphasic phenomenon with a rapid distribution followed by a slower elimination phase was observed from the plasma concentration-time curve.

Determination of wogonin in rat plasma by liquid chromatography and its pharmacokinetic application.

A high-performance liquid chromatographic method has been developed for the determination of wogonin in the rat plasma. After addition of an internal standard (clomipramine), plasma was deproteinized by acetonitrile and centrifuged for sample clean-up. The supernatant was separated by a reversed-phase column chromatography, identified by a photodiode-array detector, and quantified by ultraviolet detection at a wavelength of 275 nm. Acetonitrile-water-diethylamine (50:50:0.1, v/v/v, pH 3.0 adjusted by orthophosphoric acid) was used as the mobile phase. The method was applied to the pharmacokinetic study of wogonin in rats after a dose of mg/kg by intravenous administration. A biphasic phenomenon with a rapid distribution followed by a slower elimination phase was observed from the plasma concentration time profile.

Determination of Dihydro-5,6-Dehydrokawain in Rat Plasma by HPLC and its Pharmacokinetics Application

Abstract A simple high performance liquid chromatographic method was developed to study the pharmacokinetics of dihydro-5,6-dehydrokawain (DDK) in the rat plasma. After addition of an internal standard (osthole), plasma was deproteinized by acetonitrile for sample clean-up. The drugs were separated on a reverse phase column and detected by UV detection at a wavelength 281 nm. Acetonitrile-water-diethylamine (50:50:0.1, v/v/v, pH 3.0 adjusted by orthophosphoric acid) was used as a mobile phase. It was applied to the pharmacokinetic study of DDK in rats after a dose of 5 mg/kg intravenous administration. A biphasic phenomenon with a rapid distribution followed by a slower elimination phase was observed from the plasma concentration-time curve.

Pharmacokinetics of osthole in rat plasma using high-performance liquid chromatography

A simple high-performance liquid chromatographic method was developed to study the pharmacokinetics of osthole in rat plasma. After addition of an internal standard (paeonol), plasma was deproteinized by acetonitrile for sample clean-up. The drugs were separated on a reversed-phase column and detected by UV absorption at 323 nm. Acetonitrile-water-diethylamine (50:50:0.1, v/v/v) (pH 3.0, adjusted with orthophosphoric acid) was used as the mobile phase. It was applied to the pharmacokinetic study of osthole in rats after a dose of 10 mg kg −1 by intravenous administration. A biphasic phenomenon with a rapid distribution followed by a slower elimination phase was observed from the plasma concentration-time curve.

Pharmacokinetics of conventional formulation versus fat emulsion formulation of amphotericin B in a group of patients with neutropenia

The pharmacokinetics of amphotericin B administered in a conventional 5% dextrose (glucose) (5% D) solution and in a 20% fat emulsion formulation (Intralipid; 20% IL) were compared in 16 patients (mean age, 42 years [range, 18 to 70 years]) who had been hospitalized for hematological malignancies and with proven or suspected fungal infections. All of the patients received 50 mg (approximately 1 mg/kg of body weight per day) of amphotericin B daily in random order, either as a 50-ml lipid emulsion (20% IL) (group I) or in 500 ml of 5% D (group II). Five serum samples were taken during the 24 h after drug administration, and the levels of amphotericin B were measured by high-pressure liquid chromatography. Serum amphotericin B concentrations declined rapidly during the first 6 h, and subsequent measurements revealed a slow terminal elimination phase in both groups. The maximum serum amphotericin B concentration was significantly lower when the drug was administered in 20% IL (1.46 +/- 0.61 versus 2.83 +/- 1.17 micrograms/ml; P = 0.02). The area under the concentration-time curve from 0 to 24 h was also much lower in group I (17.22 +/- 11.15 versus 28.98 +/- 15.46 micrograms.h/ml). The half-life of the distribution phase was approximately three times longer in group I (2.92 +/- 2.34 h versus 0.64 +/- 0.24 h; P = 0.011). Conversely, the half-lives of the elimination phase were approximately equal in the two groups (11.44 +/- 5.18 versus 15.23 +/- 5.25 h). The mean residence times were also similar in both groups (19.41 +/- 11.13 versus 19.65 +/- 7.86 h). The clearance and the steady-state volume of distribution of amphotericin B in group I were about twice as great as those in group II (62.97 +/- 35.51 versus 33.01 +/- 14.33 ml/kg/h and 1,043.92 +/- 512.10 versus 562.32 +/- 152.05 ml/kg [P = 0.034], respectively). Finally, the volume of distribution in the central compartment was greater in group I than in group II (618.17 +/- 231.80 versus 328.19 +/- 151.71 ml/kg; P = 0.013), but there were no differences in the volume of distribution in the peripheral compartment (425.75 +/- 352.87 versus 234.14 +/- 75.92 ml/kg). These results suggest that amphotericin B has a different pharmacokinetic profile when it is administered in 20% IL than when it is administered in the standard 5% D form and that the main difference is due to a clear-cut difference in the steady-state volume of distribution, especially that in the central compartment.

Pharmacokinetics of cefoperazone in horses.

The pharmacokinetics and bioavailability of cefoperazone (CPZ) were studied following intravenous (IV) and intramuscular (IM) administration of single doses (30 mg/kg) to horses. Concentrations in serum, urine and synovial fluid samples were measured following IV administration. CPZ concentrations in serum, synovial fluid and spongy bone samples were measured following IM administration. After IV administration a rapid distribution phase (t1/2 (alpha): 4.22 +/- 2.73 min) was followed by a slower elimination phase (t1/2(beta) 0.77 +/- 0.19 h). The apparent volume of distribution was 0.68 +/- 0.10 L/kg. Mean synovial fluid peak concentration was 5.76 +/- 0.74 microgram/mliter. After IM administration a bioavailability of 42.00 +/- 5.33% was obtained. Half-life of absorption was 2.51 +/- 0.72 min and t1/2(beta) was 1.52 +/- 0.15 h. The mean synovial fluid and spongy bone peak concentrations at 2 h after IM administration were 2.91 +/- 0.85 microgram/mliter and 5.56 +/- 0.70 microgram/mliter, respectively.

Development and clinical application of immunoassays for european adder ( vipera berus berus) venom and antivenom

An ovine affinity purified Fab antivenom was used in a clinical trial in Sweden to treat European adder ( Vipera berus berus) envenoming. Immunoassays were developed to measure V. b. berus venom and antivenom concentrations in clinical samples to help assess the efficacy of treatment. A radioimmunoassay (RIA) was developed, optimized and validated to measure plasma levels of V. b. berus venom and compared with a conventional ELISA. Both showed a similar variation of zero binding in biological samples and the results obtained correlated closely. However, the ELISA was quicker and more sensitive (0.8 compared with 2 μg/litre). Before administration of antivenom, V. b. berus venom concentrations in plasma ranged from 10 to 53 μg/litre; 12hr after the Fab infusion, no patient had measurable levels. However, two patients had low venom levels 24 hr after treatment. ELISA and RIA were also developed, optimized and used to measure concentrations of free Fab in plasma. There was a biexponential fall of Fab concentration with a fast distribution phase ( t 1 2 = 0.9 hr ) and a slower elimination phase ( t 1 2 = 18 hr ). The amount of Fab excreted in urine was low.

Rectal methadone in cancer patients with pain: A preliminary clinical and pharmacokinetic study

Cancer pain can be treated in most cases with oral analgesics. However, during their clinical history, 53% to 70% of patients will need alternative routes of opioid administration. The rectal administration of opioids is a simple alternative route for many patients. There are no data in the literature regarding the pharmacodynamics and pharmacokinetics of rectal methadone. We evaluated the analgesia, tolerability and absorption profile of methadone hydrochloride in six opioid-naive cancer patients with pain. A blood sample was collected before administration of a single dose of drug (10 mg) and then again after fixed times. At these fixed times the patients were asked about pain, nausea and drowsiness by means of a visual analogue scale of 0-100 mm (VAS). Pain relief was statistically significant as early as 30 minutes and up to eight hours after methadone administration. None of the patients reported significant side effects. The pharmacokinetics of rectal methadone showed rapid and extensive distribution phases followed by a slow elimination phase. Rectal methadone can be considered an effective analgesic therapy for patients with cancer pain for whom oral and/or parenteral opioids are not indicated or available.

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.

Bupivacaine disposition and pharmacologic effects after intravenous and epidural administrations in dogs

SUMMARY Pharmacokinetic variables of bupivacaine (bpv) were determined after iv and epidural administrations in the same 6 dogs. Plasma bpv concentration curves after iv administration were adjusted to biexponential kinetics: a rapid distribution phase was followed by a slower elimination phase, with half-life of 34.5 ± 7.8 minutes. Mean plasma clearance was 20.2 ± 7.4 ml/min/kg of body weight, and mean volume of distribution at steady state was 0.7 ± 0.2 L/kg. After epidural administration, absorption was rapid. Peak plasma concentration, 1.4 ± 0.4 μg/ml, was detected approximately 5 minutes after bpv administration. The half-life corresponding to epidural administration (179 ± 33.6 minutes) was 5 to 6 times longer than that observed after iv administration, possibly because of the slow release of bpv from the epidural space. Induction times were short (2.3 ± 2.2 minutes); anesthesia quickly began and lasted for more than 2 hours (158 ± 48.8 minutes). During that period, bpv plasma concentration ranged between 1.4 and 0.2 μg/mi. Changes in systolic blood pressure and heart rate were correlated to high plasma concentration of bpv. These modifications were observed for the first 30 minutes, reaching baseline values after 60 minutes.

High-performance liquid chromatographic determination of evodiamine in rat plasma: application to pharmacokinetic studies.

A previously published simple and sensitive high-performance liquid chromatographic method for determination and identification of rutaecarpine in rat plasma was used for evodiamine determination. However, the ultraviolet detection was not 344 nm, but 227 nm. The method was applied to a pharmacokinetic study of evodiamine in rats after 2 mg/kg intravenous administration. A biphasic phenomenon with a rapid distribution followed by a slower elimination phase was observed from the plasma concentration-time curve. Compartmental analysis yielded a two-compartment model.