Faster absorption of ethanol and higher peak concentration in women after gastric bypass surgery

AIMS: To investigate the absorption, distribution and elimination of ethanol in women with abnormal gut as a result of gastric bypass surgery. Patients who undergo gastric bypass for morbid obesity complain of increased sensitivity to the effects of alcohol after the operation. METHODS: Twelve healthy women operated for morbid obesity at least 3 years earlier were recruited. Twelve other women closely matched in terms of age and body mass index (BMI) served as the control group. After an overnight fast each subject drank 95% v/v ethanol (0.30 g kg-1 body weight) as a bolus dose. The ethanol was diluted with orange juice to 20% v/v and finished in 5 min. Specimens of venous blood were taken from an indwelling catheter before drinking started and every 10 min for up to 3.5 h post-dosing. The blood alcohol concentration (BAC) was determined by headspace gas chromatography. RESULTS : The maximum blood-ethanol concentration (Cmax) was 0.741 +/- 0.211 g l-1 (+/- s.d.) in the operated group compared with 0.577 +/- 0.112 g l-1 in the controls (mean difference 0.164 g l-1, 95% confidence interval (CI) 0.021, 0.307). The median time to peak (tmax) was 10 min in the bypass patients compared with 30 min in controls (median difference -15 min (95% CI -10, -20 min). At 10 and 20 min post-dosing the BAC was higher in the bypass patients (P < 0.05) but not at 30 min and all later times (P > 0.05). Other pharmacokinetic parameters of ethanol were not significantly different between the two groups of women (P > 0.05). CONCLUSIONS: The higher sensitivity to ethanol after gastric bypass surgery probably reflects the more rapid absorption of ethanol leading to higher Cmax and earlier tmax. The marked reduction in body weight after the operation might also be a factor to consider if the same absolute quantity of ethanol is consumed.     

Pharmacokinetics of iloprost in patients with chronic renal failure and on maintenance haemodialysis.

Iloprost is a potent, chemically stable prostacyclin-mimetic for which therapeutic efficacy has been proven in patients with peripheral arterial occlusive disease (PAOD) and in those suffering from Raynaud's phenomenon. In volunteers and PAOD-patients the pharmacokinetics of iloprost after intravenous (i.v.) infusion treatment was characterized by dose-dependent steady-state plasma levels, a terminal half-life of approximately 20-30 min, and a total clearance of 15-20 ml/min/kg. Bioinactivation was mainly due to beta-oxidation. In the present study the pharmacokinetics of iloprost was investigated in 21 patients suffering from renal insufficiency, which either required haemodialysis or not. They were treated by one hour i.v. infusion with 1 ng/kg/min and blood samples were taken during and after the end of infusion. Due to technical sampling problems iloprost pharmacokinetics could only be calculated for seven dialysis and eight non-dialysis patients. In the dialysis patients steady-state levels were 114 to 320 pg/ml as compared to 36 to 70 pg/ml in the non-dialysis group. Half-lives were similar in both groups: alpha-phase: 0.05 h and beta-phase: 0.5 h. The total clearance was 2.6 to 8.0 ml/min/kg (dialysis patients) and 13.2 to 25.8 ml/min/kg (non-dialysis patients). The present study demonstrated that the pharmacokinetic profile of iloprost in patients with renal failure (not subject to haemodialysis) was similar to that observed in PAOD-patients and volunteers. In patients on maintenance haemodialysis, iloprost clearance was reduced by a factor of four. The iloprost dose regimen required in general (due to interindividual variability in response) a careful dose titration.     

Pharmacokinetics of trimethylamine in rats, including the effects of a synthetic diet.

1. The pharmacokinetic profile of trimethylamine (TMA) was examined in the male Wistar rat and the effects of a synthetic diet on TMA pharmacokinetics were also evaluated. 2. The concentrations of TMA and its N-oxide in blood were analysed by a sensitive headspace gas chromatographic assay. 3. The pharmacokinetics of TMA were essentially linear for intravenous (i.v.) bolus doses of 10-40 mg kg(-1). Over the range of administered i.v. doses, the concentrations of TMA in blood declined approximately monoexponentially with half-lives of 2.03-2.48 h. The Vd of TMA ranged from 3.2 to 4.39 l kg(-1) and clearance ranged from 18.78 to 23.92 ml min(-1) kg(-1). The peak concentration of TMA in blood occurred at 1 h after oral administration of a 20 mg kg(-1) dose and the bioavailability for the oral dose averaged 81%. 4. Peak concentrations of trimethylamine N-oxide (TMAO) in blood were attained at 0.73 and 1 h after i.v and oral administration of TMA (20 mg kg(-1)), respectively. 5. Feeding the male Wistar rat with a synthetic diet resulted in a twofold decrease in the clearance of TMA. Furthermore, the concentration of TMAO in blood after i.v. administration of TMA peaked at 1.25 h in rat placed on the synthetic diet as opposed to 0.75 h in rat placed on normal laboratory rat chow. The altered pharmacokinetic profile of TMA and its N-oxide suggest a diminished drug-elimination capacity in rat placed on the synthetic diet. 6. Dietary modulation of flavin-containing monooxygenase (FMO) activity may explain the effects of diet on the pharmacokinetics of TMA and its N-oxide.     

Ethanol preference following hypothalamic stimulation: relation to stimulation parameters and energy balance

Rats were given 5, 10, 20 and 30 min daily sessions of lateral hypothalamic stimulation. Approximately half of the rats showed a large and highly significant increase in their total intake of and preference for 10% v/v ethanol which was continuously available in their home cages. In terms of latency, total consumption and preference for ethanol, 10 min of daily stimulation produced a much greater enhancement than did 30 min. The ethanol drinking rats used more energy per unit of body weight which suggests that the stimulation and/or the ethanol itself may have increased energy expenditure. Simply changing the diet from powdered chow to identical composition pellets produced a large reduction in both total ethanol intake and preference. Reinstating the powdered diet produced a rapid reinstatement of ethanol drinking. These data are discussed in terms of ethanol's role in modulating stimulation induced changes in energy balance.     

Impact of gastric emptying on the pharmacokinetics of ethanol as influenced by cisapride

AIMS: To examine the influence of cisapride on the pharmacokinetics of ethanol and the impact of gastric emptying monitored by the paracetamol absorption test. METHODS: Ten healthy male volunteers took part in a cross-over design experiment. They drank a moderate dose of ethanol 0.30 g kg-1 body weight exactly 1 h after eating breakfast either without any prior drug treatment or after taking cisapride (10 mg three times daily) for 4 consecutive days. In a separate study, the same dose of ethanol was ingested on an empty stomach (overnight fast). Paracetamol (1.5 g) was administered before consumption of ethanol to monitor gastric emptying. Venous blood was obtained at 5-10 min intervals for determination of ethanol by headspace gas chromatography and paracetamol was analysed in serum by high performance liquid chromatography (h.p.l.c.). Results The maximum blood-ethanol concentration (Cmax ) increased from 3.8+/-1.7 to 5.6+/-2.3 mmol l-1 (+/-s.d.) after treatment with cisapride (95% confidence interval CI on mean difference 0.28-3.28 mmol l-1 ). The area under the blood-ethanol curve (AUC) increased from 6.3+/-3.5 to 7.9+/-2.6 mmol l-1 h after cisapride (95% CI -0. 74-3.9 mmol l-1 h). The mean blood ethanol curves in the cisapride and no-drug sessions converged at approximately 2 h after the start of drinking. Both Cmax and AUC were highest when the ethanol was ingested on an empty stomach (Cmax 9.5+/-1.7 mmol l-1 and AUC 14. 6+/-1.9 mmol l-1 h), compared with drinking 1 h after a meal and regardless of pretreatment with cisapride. CONCLUSIONS: A small but statistically significant increase in Cmax occurred after treatment with cisapride owing to faster gastric emptying rate as shown by the paracetamol absorption test. However, the rate of absorption of ethanol, as reflected in Cmax and AUC, was greatest after drinking the alcohol on an empty stomach. The cisapride-ethanol interaction probably lacks any clinical or forensic significance.     

Combination of low dose ethanol and caffeine protects brain from damage produced by focal ischemia in rats

Caffeine and ethanol are two commonly overused psychoactive dietary components. The purpose of this study was to assess the effects of acute, chronic, oral (p.o.) and intravenous (i.v.) caffeine, ethanol and their combination on infarct volume following focal ischemia in rats. Rats received treatment either p.o. 3 h and 1 h before, or by i.v. infusion for 2.5 h beginning 30-180 min after, ischemia. There were six acute treatment groups. (1) oral dH2O (control); (2) oral caffeine (10 mg/kg); (3) oral ethanol (0.65 g/kg total); (4) oral ethanol plus caffeine; (5) intravenous saline; and (6) intravenous ethanol (0.65 g/kg) plus caffeine (10 mg/kg) in saline. A 7th group received oral ethanol plus caffeine for three weeks prior to ischemia. After 3 h of left MCA/CCA occlusion and 24 h reperfusion, infarct volume was determined. Control animal infarct volume was 102.4+/-42.0 mm3. Oral caffeine alone had no effect (122.4+/-30.2 mm3). Oral ethanol alone exacerbated infarct volume (177.2+/-27.8 mm3). Oral caffeine plus ethanol almost entirely eliminated the damage (17.89+/-10.41 mm3). When i.v. treatment with ethanol plus caffeine was initiated at 30, 60, 90 and 120 minutes post-ischemia the infarct volume was reduced by 71.7%, 49.8%, 64.8% and 47.1%, respectively. Chronic daily oral ethanol plus caffeine prior to ischemia eliminated the neuroprotection seen with acute treatment. These studies indicate that ethanol, which by itself aggravates cerebral ischemia, and caffeine, when combined together immediately before or for 2 h after focal stroke, reduces ischemic damage.     

Verapamil worsens ethanol-induced gastric ulcers in rats

The effect of verapamil on ethanol-induced gastric ulceration was investigated in rats. Orally administered ethanol (0.5 ml), 10, 20 or 40% v/v, dose dependently produced glandular lesions, ranging from petechiae to haemorrhagic ulcers. These lesions were worsened by verapamil (2, 4 or 8 mg/kg given intraperitoneally (i.p.) 30 min beforehand) in the 30 min and 2 h ethanol-exposure experiments. However, ethanol ulceration or its aggravation by verapamil was antagonised by calcium gluconate (112 or 224 mg/kg given per os (p.o.) 30 min before ethanol administration) in a dose-related manner. These findings suggest that intracellular calcium depletion in the gastric glandular mucosa may account for ethanol ulceration and the ulcer-aggravating action of verapamil.     

Nisoldipine: Kinetics and effects on blood pressure and heart rate in patients with liver cirrhosis after intravenous and oral administration

Summary The pharmacokinetics and effects on blood pressure and heart rate of nisoldipine were studied in 8 patients with cirrhosis and in 8 age-matched healthy controls. On separate occasions each subject received nisoldipine by i.v. infusion (0.37 mg in 40 min) and as a tablet (5 mg for patients and 20 mg for control subjects).After i.v. nisoldipine, the elimination half-life was 9.7 h in control subjects and 16.6 h in the cirrhotics. The volume of distribution was 4.1 l/kg and 6.4 l/kg and the total systemic clearance was 847 ml/min and 494 ml/min, respectively. On oral nisoldipine, systemic availability was fourfold higher in patients with cirrhosis: 14.7% versus 3.7%.After i.v. administration of nisoldipine there was a brief decrease in systolic and diastolic blood pressure in both groups, whereas the heart rate increased. After 4 h a second effect peak appeared in the control subjects. After oral nisoldipine similar effect-time profiles were found, but effects lasted longer than after i.v. administration.Comparison of the maximal total plasma concentration of nisoldipine and the maximal effect in the two groups revealed that sensitivity to nisoldipine was not different in patients with cirrhosis.A reduction in the dose of nisoldipine is recommended when cirrhotics require oral nisoldipine in therapeutic practice.     

Pharmacokinetics of trimethylamine in rats,including the effects of a synthetic diet

1. The pharmacokinetic profile of trimethylamine (TMA) was examined in the male Wistar rat and the effects of a synthetic diet on TMA pharmacokinetics were also evaluated. 2. The concentrations of TMA and its N -oxide in blood were analysed by a sensitive headspace gas chromatographic assay. 3. The pharmacokinetics of TMA were essentially linear for intravenous (i.v.) bolus doses of 10-40?mg kg -1. Over the range of administered i.v. doses, the concentrations of TMA in blood declined approximately monoexponentially with half-lives of 2.03-2.48?h. The V d of TMA ranged from 3.2 to 4.39?l kg -1 and clearance ranged from 18.78 to 23.92ml?min -1 kg -1. The peak concentration of TMA in blood occurred at 1?h after oral administration of a 20?mg kg -1 dose and the bioavailability for the oral dose averaged 81%. 4. Peak concentrations of trimethylamine N -oxide (TMAO) in blood were attained at 0.75 and 1?h after i.v and oral administration of TMA (20mg kg -1), respectively. 5. Feeding the male Wistar rat with a synthetic diet resulted in a twofold decrease in the clearance of TMA. Furthermore, the concentration of TMAO in blood after i.v. administration of TMA peaked at 1.25?h in rat placed on the synthetic diet as opposed to 0.75?h in rat placed on normal laboratory rat chow. The altered pharmacokinetic profile of TMA and its N -oxide suggest a diminished drug-elimination capacity in rat placed on the synthetic diet. 6. Dietary modulation of flavin-containing monooxygenase (FMO) activity may explain the effects of diet on the pharmacokinetics of TMA and its N -oxide.     

芍药甙的药代动力学研究

芍药是白芍的主要成份,狗iv芍药甙11.25mg/kg后,血药浓度曲线符合二室模型。动力学参数:T_(1/2)(α)为6.29±1.80min,T_(1/2)(β)为133.41±84.89min,VB为0.54±0.10L/kg,CL为3.41±1.01ml/kg·min~(-1)。本品静注后迅速以原型出现于尿中,前20min和7h尿中累积排泄量占静注量分别为36.85%和79.33%,7h胆汁中累积排泄量占静注量为3.77%     

Induction and maintenance of ethanol self-administration without food deprivation in the rat

Rats were trained to lick at a drinking tube containing 5% ethanol to obtain access to a 0.1-ml dipper containing 20% sucrose. Following 20 of these drinking sessions, a lever press response was shaped and maintained with ethanol presentation in the dipper. This induction procedure resulted in rats responding on a FR 8 schedule of reinforcement to receive 40% (v/v) ethanol. Ethanol intakes over 0.5 g/kg in 30 min were obtained when ethanol concentrations over 10% were available. These intakes frequently resulted in blood ethanol levels over 100 mg ethanol/dl blood. This contingent sucrose induction procedure did not use food deprivation at any time. It is suggested that this procedure can be used to investigate the processes involved with the initiation of ethanol as a reinforcer independent of food restriction procedures.     

Pharmacokinetics of entacapone, a peripherally acting catechol-O-methyltransferase inhibitor, in man

OBJECTIVE: This study investigated the pharmacokinetics of the catechol-O-methyltransferase (COMT) inhibitor entacapone by giving simultaneously stable non-radioactive isotope 13C-entacapone intravenously (i.v.) and unlabelled entacapone orally. In comparison with a crossover design, the simultaneous i.v. and oral administration made it possible to minimise intra-individual variation, sample size and the duration of the study and still obtain accurate pharmacokinetic data. METHODS: Eight healthy male volunteers were enrolled in this study. They were given a 20-mg i.v. dose of 13C-entacapone as a 1-mg/ml infusion at a constant rate of 5 mg/min over 4 min and a 100-mg dose of unlabelled entacapone orally immediately after the infusion. Blood samples were drawn at -5 (before onset of infusion), 0 (upon termination of infusion), 2, 5, 10, 20, 30 and 45 min and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10 and 12 h after the tablet ingestion. Urine during the 48 h after dosing was collected in fractions. Concentrations of 13C-entacapone and entacapone in plasma samples and urine fractions were determined using gas chromatography-mass spectrometry. RESULTS: The decay of i.v. 13C-entacapone in plasma was tri-exponential and its pharmacokinetics were described using an open three-compartment model. The volume of the central compartment (Vc) and the volume of distribution at steady state (Vss) were 0.08+/-0.03 l/kg and 0.27+/-0.10 l/kg, respectively. Total plasma clearance (Cltot) averaged 11.7+/-1.9 ml/min kg(-1). The half-lives for the distribution phase and for the rapid and terminal elimination phases (t1/2alpha, t1/2beta and t1/2gamma) were 0.05+/-0.01 h, 0.38+/-0.16 h and 2.40+/-1.70 h, respectively. The terminal elimination phase accounted for only 9% of the total area under the plasma concentration-time curve (AUC), which was 409 +/- 98 ng h/ml after the i.v. dose. Oral entacapone was absorbed rapidly with a time to reach the peak concentration (tmax) of 0.9+/-0.4 h, a maximum concentration (Cmax) of 457+/-334 ng/ml and an AUC of 497+/-118 ng h/ml. During the 48 h after dosing, the recovery of free and conjugated unchanged 13C-entacapone in urine was 38.1+/-7.2% of the i.v. dose and the recovery of free and conjugated unchanged entacapone 13.3+/-3.9% of the oral dose. The bioavailability of oral entacapone was 25% based on the AUC values and 35% based on urinary excretion. CONCLUSION: The results of the present study using stable isotope technique indicate that entacapone is rapidly absorbed, distributed to a small volume and rapidly eliminated by mainly non-renal routes. The pharmacokinetic profile of entacapone provides the rationale for a concomitant and frequently repeated simultaneous dosing of entacapone with levodopa and dopa decarboxylase inhibitors in the treatment of Parkinson's disease. This study confirmed the previously published data and fully support the validity of the technique used.     

Biodistribution and pharmacokinetics of variously sized molecular radiolabelled polyethyleneiminomethyl phosphonic acid as a selective bone seeker for therapy in the normal primate model

An ideal radiopharmaceutical for the treatment of neoplastic and inflammatory (benign) bone disease would be a radiolabelled compound that predominantly accumulates in bone lesions with limited access to normal bone and other organs. Neoplastic tissue's abnormal blood supply (increased permeability) and lack of lymphatics will selectively accumulate radiolabelled macromolecules. This enhanced permeability and retention effect forms the basis of this study, using various molecular sizes of the radiolabelled macromolecule polyethyleneiminomethyl phosphonic acid (PEI-MP) for increased selectivity of the bone-seeking radiopharmaceutical. PEI-MP was synthesized by condensation of polyethyleneimine, phosphonic acid and formaldehyde, followed by fractionation into different molecular sizes by membrane ultrafiltration. Labelling efficiency to 99mTc (as radiotracer) was approximately 99% with complexes stable for 24 h. The pharmacokinetics and biodistribution of various 99mTc-PEI-MP fractions were investigated using 4 experimental baboons (Papio ursinus) per fraction. Scintigraphy was performed on the baboons under general anaesthesia of pentobarbital i.v. After an i.v. bolus of 99mTc-PEI-MP (approximately 185 MBq) both dynamic studies (30 x 1 min frames), and static studies (2 min acquisition every hour for 4 h) were done, as well as blood samples and urine collected. From the results macromolecules with sizes ranging between 30-300 kDa were characterized by excessive liver (21%-57% retained activity) and kidney (40% retained activity) uptake and accompanying long residing times (t1/2 up to 24 h). The percentage bone uptake averaged at 8% for these particles excluding sizes 100-300 kDa where very little bone uptake was seen (< 1%). In this case the blood clearance was also slow (t1/2 approximately 2 h). The fraction size 10-30 kDa had comparatively low accumulation and short residence times in the liver and kidneys (resp. 20%, t1/2 = 22 +/- 4 min; 17.5%, t1/2 = 20 +/- 3 min) and although the bone uptake of 18% in this case was high, it is still low for a bone-seeking agent. These particles cleared the blood with t1/2 = 25 +/- 2 min and seemed suitable for labelling with a therapeutic radioisotopic agent.     

Bioavailability of dihydroergotamine in man.

1 The pharmacokinetics of dihydroergotamine (DHE) in plasma were examined in six normotensive subjects after single acute doses of dihydroergotamine, 10 micrograms/kg i.v. and 10, 20 and 30 mg orally. 2 The mean apparent half-time of elimination was 2.37 +/- 0.29 h and plasma clearance of dHE was 1002 +/- 169 ml/min. 3 Mean apparent absorption of DHE determined from the 10 mg dose was 26.6 +/- 10% and ranged from 8.9 to 60.3%. The oral bioavailability after the 10, 20 and 30 mg doses averaged 0.47 +/- 0.07%, 0.59 +/- 0.13% and 0.52 +/- 0.14% respectively. Inter-patient variability in bioavailability was 6-fold. 4 The results indicate that pre-systemic 'first-pass' extraction of DHE is the main determinant of its oral bioavailability. Oral doses of the drug up to 30 mg do not saturate this extraction process resulting in apparently linear kinetics for the drug.     

Pharmacokinetics of intravenous and oral L-arginine in normal volunteers

AIMS: Recent studies in patients with cardiovascular diseases suggest potential for the use of orally administered L-arginine, the precursor of nitric oxide, as a therapeutic agent. This crossover study was designed to examine the pharmacokinetics of single i.v. and oral doses of L-arginine in healthy volunteers (n = 10). METHODS: A preliminary control study (n = 12) was performed to assess the variation in plasma L-arginine concentrations when ingesting a normal diet. The observed variation was taken into account when interpreting the pharmacokinetic data obtained after exogenous administration. RESULTS: The mean baseline plasma concentration of L-arginine in the control study was 15.1+/-2.6 microg ml(-1). After intravenous administration (30 g over 30 min), the plasma concentration reached 1390+/-596 microg ml(-1). The disappearance of l-arginine appeared biphasic, with an initial rapid disappearance due to concentration-dependent renal clearance followed by a slower fall in plasma concentrations due to nonrenal elimination. The peak concentration after oral administration (10 g) was 50.0+/-13.4 microg ml(-1), occurring 1 h after administration. Renal elimination was not observed after oral administration of this dose. The absolute bioavailability of a single oral 10 g dose of L-arginine is approximately 20%. CONCLUSIONS: This study provides basic knowledge of L-arginine pharmacokinetics in healthy humans. Intravenous and oral administrations show at minimum a biphasic pattern. Further studies will assess whether a similar profile is observed when the drug is administered to patients.     

Regional metabolism of articaine in 10 patients undergoing intravenous regional anaesthesia during day case surgery

Aims To study the pharmacokinetics of articaine and its metabolite articainic acid, in patients undergoing intravenous regional anaesthesia.
Methods Ten patients (three male, seven female, ASA class 1–2), scheduled for surgery of the hand or forearm were included in the study. Articaine (40  ml, 0.5% solution (200  mg) was injected over 30 s. In total fifteen arterial blood samples were taken; one before injection and then at 10 min intervals, starting 10  min after completion of injection, until the tourniquet was released; thereafter blood samples were drawn at intervals of 1, 5, 10, 15, 20, 25, 30, 45, 60, 75 and 90 min. The tourniquet was released 30  min after completing the injection.
Results During tourniquet application and regional analgesia of 30  min duration, 55% of articaine was hydrolysed by plasma (20%) and tissue (35%) esterase activity to the metabolite articainic acid. After releasing the tourniquet, articaine and its metabolite appeared in the blood; articaine was rapidly eliminated with a t_1/2z of approximately 60  min. The plasma concentration of the metabolite articainic acid was the sum of the amount formed during IVRA (55%) and the amount formed after tourniquet release (45%).
Conclusions Articaine is a safe agent for intravenous regional anaesthesia (IVRA) with rapid onset of good surgical anaesthesia. During tourniquet application and regional analgesia, 55% of the administered dose is already hydrolysed, thus reducing the chance of side effects after tourniquet release.     

A review of the clinical pharmacokinetics and metabolism of the alpha 1-adrenoceptor antagonist indoramin

1. The alpha 1-adrenoceptor antagonist indoramin is rapidly and extensively absorbed after oral administration, but with only low to moderate bioavailability (8-24% median) from the tablet (Baratol). Although plasma protein binding is high (72-86%), the drug is widely distributed into tissues (with median Vz 6.3-7.7 l/kg after i.v. dosage). 2. Elimination of indoramin is rapid in most healthy volunteers, with median plasma clearances of 18-26 ml/min per kg, after i.v. dosage. Elimination occurs principally by metabolism, the major route being indole 6-hydroxylation, followed by sulphate conjugation of 6-hydroxyindoramin. The faecal route of excretion predominates (45-50% of dose), with a further 35-40% in the urine. 3. Extensive variation in single-dose oral pharmacokinetics of indoramin is due largely to the existence of a poor metabolizer phenotype which co-segregates with that of debrisoquine. 4. On repeated administration (37.5 mg twice daily) to healthy volunteers, plasma concentrations of indoramin accumulate 3-4-fold above those anticipated from single-dose kinetics. However, steady state is achieved within the first week of dosing. 5. The pharmacokinetics of indoramin are substantially altered in the elderly. The oral AUC for a 50 mg dose is increased approx. 5-fold and the t1/2 2.5-fold. 6. Cirrhotic liver disease enhances bioavailability and decreases clearance, approx. 2-fold in each case for single oral and i.v. doses of 50 mg and 0.15 mg/kg respectively. 7. After oral indoramin Cmax and AUC are both raised (58% and 25%, respectively, for a 50 mg dose) by co-ingested ethanol (0.5 g/kg). After i.v. indoramin, kinetics are unaffected by alcohol, but indoramin (0.175 mg/kg) slightly increases (26%) blood ethanol concentrations during the first hour after dosing. 8. The pharmacodynamics of indoramin appear to be related to the combined pharmacokinetics of the drug and its 6-hydroxylated metabolite, which contributes to the antihypertensive effect.     

Quantitative determination of amantadine in human plasma by liquid chromatography-mass spectrometry and the application in a bioequivalence study

A sensitive liquid chromatography-electrospray ionization mass spectrometry (LC-ESI-MS) method is developed and validated for rapid determination of amantadine in human plasma. Desloratadine was used as the internal standard (I.S.). Human plasma (0.2 mL) was first alkalified with 100 microL of sodium hydroxide (3M) and then extracted with 1 mL of n-hexane containing 1% isopropanol (v/v) and 10% dichloromethane (v/v) by vortex-mixer for 3 min. The mixture was centrifuged at 14,000 rpm for 5 min. The supernatant was evaporated to dryness and the residue was dissolved in mobile phase. Samples were separated using a Thermo Hypersil-HyPURITYC18 reversed-phase column (150 mm x 2.1 mm i.d., 5 microm). Mobile phase consisted of methanol-acetonitrile-20 mM ammonium acetate (45:10:45, v/v/v) containing 1% acetic acid with pH 4.0. Amantadine and I.S. were measured by electrospray ion source in positive selective ion monitoring mode. The good linearity ranged from 3.9 to 1000 ng/mL and the lowest limit of quantification was 3.9 ng/mL. The extraction efficiencies were approximately 70% and recoveries of method ranged from 98.53 to 103.24%. The intra-day relative standard deviations (R.S.D.) were less than 8.43% and inter-day R.S.D. below 10.59%. The quality control samples were stable when kept at room temperature for 12h, at -20 degrees C for 30 days and after four freeze/thaw cycles. The method has been successfully used to evaluation of the pharmacokinetics and bioequivalence of amantadine in 20 healthy volunteers after an oral dose of 100 mg amantadine.     

Lack of operant ethanol self-administration in dopamine D2 receptor knockout mice

RATIONALE: Dopamine D2 receptors are postulated to play an important role in modulating the reinforcing effects of abused drugs including ethanol. OBJECTIVES: This experiment examined operant ethanol self-administration in dopamine D2 receptor knockout (KO) mice and wild-type (WT) mice using a continuous access procedure. METHODS: Adult male KO and WT mice were trained in 30-min sessions to perform a lever press response for access to 10% v/v ethanol. After training, the mice were placed in test chambers on a continuous (23 h/day) basis with access to food (one lever press, i.e., FR1), 10% v/v ethanol (four lever presses, i.e., FR4), and water from a sipper tube (phase 1). After 30 consecutive sessions, response patterns were determined for 0, 5, 10, 20 and 30% v/v ethanol (phase 2). Saccharin (0.2% w/v) was subsequently added to the ethanol mixture and responding was examined for 0, 5, 10 and 20% ethanol (phase 3). RESULTS: During phase 1, WT mice displayed higher ethanol-lever responding compared to KO mice. Food lever responding and water intake was the same in both genotypes. During phase 2, WT mice displayed concentration-dependent ethanol lever responding, whereas KO mice responded at low rates regardless of ethanol concentration. WT mice also responded more for food compared to KO mice. Each genotype showed similar water intakes except at the 20% ethanol concentration, where WT mice had lower intakes. During phase 3, WT mice continued to show higher responding for all concentrations including saccharin alone. WT mice also continued to respond more for food compared to KO mice, but drank less water. In each phase, WT mice displayed episodic (bout) responding on the ethanol lever. KO mice did not respond for ethanol in bouts. CONCLUSIONS: Reduced responding in the KO mice for several reinforcers including ethanol indicates a more general role for dopamine D2 receptors in motivated responding rather than a specific role in ethanol reinforcement.     

Pharmacokinetic study of a new semisynthetic cephalosporin (AL-226) in rabbits

The pharmacokinetics of AL-226, a new semi-synthetic cephalosporin, were studied after i.v. and i.m. administrations to rabbits at doses of 10, 20, 30 and 40 mg/kg. The average values of the pharmacokinetic parameters after bolus i.v. administration of the antibiotic expressed by an open two-compartment kinetic model were: alpha = 0.131 min.-1, beta = 0.0341 min-1, K12 = 0.0287 min.-1, K21 = 0.0552 min.-1, K13 = 0.081 min.-1 a linear relationship between C0 and dose was found. The urinary excretion constants after i.v. administration were: 0.0266 min.-1, 0.0294 min-1, 0.0289 min.-1, 0.0306 min.-1, for doses of 10, 20, 30 and 40 mg/kg, respectively. The pharmacokinetic parameters after i.v. administration were used to determine the absorption constant: 0.0525 min.-1, 0.057 min.-1, 0.0596 min.-1, 0.0511 min.-1, after i.m. administration for doses of 10, 20, 30 and 40 mg/kg, respectively.