Diazinon toxicokinetics, tissue distribution and anticholinesterase activity in the rat

The toxicokinetics, tissue distribution, and anticholinesterase (antiChE) activity of diazinon were investigated in the rat. Plasma concentrations most adequately fitted a two-compartment open model after i.v. administration of 10 mg/kg and a one-compartment model after oral administration of 80 mg/kg. Diazinon elimination half-life following i.v. and oral dosing was 4.70 and 2.86 h, respectively. The oral bioavailability was found to be low (35.5%). Hepatic extraction ratios after i.v. administration of 5 or 10 mg/kg were 54.8% and 47.7%, respectively, suggesting that low systemic oral bioavailability can be explained by a first-pass effect in the liver. Diazinon was found to be approximately 89% protein-bound in plasma within the concentration range 0.4-30 ppm. The highest concentration of diazinon after i.v. administration was found in the kidneys, when comparing to liver, kidney, brain. Both red blood cell (RBC) acetylcholinesterase (AChE) and plasma ChE activities were inhibited rapidly (44% and 17% at 10 min, and 36% and 13% min for i.v. and oral administration, respectively), but inhibition of RBC AChE was greater than that of plasma ChE.     

Aging and ethanol metabolism

The effect of aging on the distribution and elimination of ethanol was studied in a group of 50 healthy subjects ranging in age from 21 to 81 yr (mean, 53.3). Ethanol was administered in a continuous 1-hr infusion at a mean rate of 375 mg/m2 body surface area/min (equivalent to a mean dose of 0.57 gm/kg body weight). Serial blood samples for the determination of ethanol concentration was obtained at 15- to 30-min intervals for up to 4 hr post infusion. Ethanol elimination and distribution were evaluated with the aid of a two-compartment model. Rates of ethanol elimination were not affected by age. Peak ethanol concentration in blood water at the end of the infusion period was correlated with age (r= 0.55, p less than 0.001). Lean body mass and total volume of distirbution fo the ethanol were negatively correlated with age. The smaller volume of distirbution, in association with the decreased lean body mass, most likely explains the higher peak ethanol concentration found in the blood after administration of an ethanol does on the basis of surface area in the old as compared with the young subjects. This study demonstrates that age-related changes in body composition are important factors in the study of ethanol metabolism and its pharmacologic effects.     

Pharmacokinetic study of nerisopam and its n-acetyl metabolite in rats

Three doses were administered to the rats during the pharmacokinetic study of nerisopam and the plasma concentrations of nerisopam and its N-acetyl metabolite were determined parallelly by means of validated SPE-HPLC method developed by the authors. The pharmacokinetics of nerisopam could be described by a two-compartment open model in rats, it was absorbed rapidly and could be measured in plasma for about 8 hours. The peak plasma concentration of the N-acetyl metabolite was reached rapidly a little bit later than that of the parent compound, similarly to the human plasma, and it could be measured for about 12 hours. The pharmacokinetics of N-acetyl metabolite could be described by an one-compartment open model. The fast appearance of the metabolite and the Cmax and AUC 0-infinity values higher than those of nerisopam refer to an intensive "first-pass" metabolism. The AUC-dose curves indicate that supposingly the mechanism transforming the N-acetyl metabolites are not as fast as the acetylation.     

Development and application of a physiologically based pharmacokinetic model for ethanol in the mouse

The purpose of the present study was to develop a physiologically based pharmacokinetic (PBPK) model in the mouse and to utilize it to evaluate the relative contribution, if any, of gastric alcohol dehydrogenase (ADH) to the bioavailability of ethanol. The PBPK model developed in Swiss Webster male mice accurately simulated blood and brain ethanol concentrations following an intraperitoneal administration of 0.82 and 3.2 g of ethanol/kg body weight. Application of the model illustrated that inclusion of gastric ADH into the model provided a less accurate fit to the experimental data, and therefore gastric ADH did not contribute to the overall disposition of an orally administered ethanol dose of 0.75 g/kg. Furthermore, the model also indicated that changes in percentage cardiac output to the liver had a minimal effect on the blood ethanol concentration (BEC) time curve. The results illustrate the validity of the PBPK model developed for ethanol and demonstrate that in the Swiss Webster male mouse the bioavailability of ethanol is minimally affected, if at all, by metabolism by gastric ADH.     

Effect of methylmercury on the ethanol elimination from the blood and the activity of alcohol dehydrogenase

In an attempt to assess the effects of methylmercury on ethanol metabolism, Sprague-Dawley rats were treated with a daily dose (10 mg/kg i.p.) of methylmercuric chloride for 2 consecutive days and given a test dose (0.4 g/kgi.v.) of ethanol 24 hr after the last treatment. Blood ethanol levels were measured using gaschromatography by the direct introduction of blood samples into the sample vaporizing apparatus attached to the chromatograph. While treatment with methylmercury elicited a slight retardation in the ethanol elimination from the blood during 30 to 90 min, methylmercury did not essentially alter ethanol metabolism. There was no significant change in hepatic alcohol dehydrogenase activity of methylmercury-treated rats. By contrast, the activity of alcohol dehydrogenase purified from liver or yeast was remarkably inhibited by methyl-mercury and the type of inhibition proved to be non-competitive. Moreover, the inhibited activity was reactivated easily by sulfhydryl agents. From these results, it is conceivable that methylmercury has little influence on ethanol metabolism in vivo because of its non-specific binding with sulfhydryl groups in the organism.     

Comparison of 5-fluorouracil pharmacokinetics in whole blood, plasma, and red blood cells in patients with colorectal cancer

STUDY OBJECTIVE: To compare 5-fluorouracil (5-FU) pharmacokinetics in whole blood, plasma, and red blood cells in patients with colorectal cancer. DESIGN: Prospective, unblinded observational study in consecutive patients. SETTING: Large regional teaching hospital. PATIENTS: Five patients with colorectal cancer. INTERVENTIONS: Patients received folinic acid 200 mg/m2 intravenously over 2 hours, followed by 5-FU 600 mg/m2 intravenous bolus over 30 minutes, then 5-FU 600 mg/m2 intravenous infusion over 22 hours, administered on days 1 and 2. This 48-hour cycle was repeated every 14 days. MEASUREMENTS AND MAIN RESULTS: Concentrations of 5-FU in whole blood, plasma, and red blood cells were determined by high-performance liquid chromatography. ADAPT II was used for pharmacokinetic computations. The optimum model was determined for each matrix by calculating Akaike's information criteria values. Concentrations of 5-FU in whole blood were 106-115% of simultaneous plasma concentrations (median 112%), and packed red blood cell levels were 5-17% of plasma concentrations (median 11%). The drug's concentration-time profile was similar in the three matrices. The drug is reported to be unstable in whole blood, and red blood cell 5-FU concentrations were near the limit of detection (10 ng/ml), supporting plasma as the preferred matrix for therapeutic drug monitoring studies. Six pharmacokinetic models were fitted to the 5-FU individual data sets to determine the best curve fit. The optimal model for whole blood and plasma data sets was one compartment with both linear and nonlinear elimination models; a one-compartment model with nonlinear elimination provided the best curve fit for 5-FU in red blood cells. A two-compartment model with nonlinear elimination gave a similar degree of curve fit for plasma 5-FU as the one-compartment model with both linear and nonlinear elimination. CONCLUSIONS: These pharmacokinetic results provide the basis for further investigation into the ability to correlate 5-FU systemic exposure with clinical drug activity.     

Pharmacokinetic analysis program based on tank-in-series model, MULTI(TIS), for evaluation of capacity-limited local disposition

A pharmacokinetic analysis program based on a tank-in-series model, MULTI(TIS), was developed for the evaluation of dose-dependency in the local disposition of a drug. The program written in FORTRAN was constructed by expanding MULTI(RUNGE). The reliability of MULTI(TIS) was verified by analyzing the experimental data based on linear and nonlinear tank-in-series models. Linear one- and two-compartment tank-in-series models were adopted to analyze outflow time profiles in single-pass hepatic perfusion following a pulse input of 5'-deoxy-5-fluorouridine (DFUR). The estimated parameters agreed well with those by MULTI(FILT) which is widely used for linear kinetic analysis. The nonlinear models adopted were one-compartment model with Michaelis-Menten elimination and two-compartment models with Michaelis-Menten elimination from central and peripheral compartments. Oxacillin was used as a model drug, because time courses of oxacillin show a capacity-limited hepatic disposition following a pulse input in high doses to the liver (300, 1000, 3000 and 5000 microg). The hepatic recovery ratio (F(H)) of oxacillin increased with dose, whereas the mean transit time (tH) was almost constant. The maximum elimination rate constant (Vmax) and Michaelis constant (Km) of oxacillin were estimated to be 1980 microg/ml/min and 54.1 microg/ml, respectively. Thus, the reliability of MULTI(TIS) was demonstrated for the analysis of nonlinear local disposition, especially, capacity-limited elimination in the liver.     

Pharmacokinetic studies of pentylenetetrazol in dogs

Pharmacokinetic profiles of pentylenetetrazol in the dog were studied following rapid intravenous and oral administrations of a convulsant dose (15-20 mg/kg). Plasma level-time curves after a rapid intravenous injection showed biexponential decline, indicating that the disposition of this drug in the dog follows a two-compartment body model. Pharmacokinetic parameters were calculated from the intravenous data. After oral administration of the solution dose, the peak plasma level appeared at about 30 min postdose, indicating that the absorption occurs rapidly. Areas under the oral plasma level-time curves s howed that the drug was absorbed completely and that the first-pass metabolism effect was minimal. The ligation studies of the kidney and the liver suggested that the main elimination pathway of this drug was biotransformation in the liver. The average plasma half-life was 1.4 hr. At steady state, the volume of distribution was approximately equivalent to the volume of the total body water.     

Cocaethylene formation following ethanol and cocaine administration by different routes.

Ethanol alters the hepatic biotransformation of cocaine, resulting in transesterification to a novel active metabolite, cocaethylene. Because of first pass metabolism, oral drug administration might be expected to produce relatively larger concentrations of cocaethylene than would intravenous or smoked administration. We, therefore, compared the effects of route of cocaine administration on the formation and elimination of cocaethylene. Six experienced cocaine users were tested in 6 sessions, approximately 1 week apart. Deuterium-labeled cocaine (d?) was administered in all conditions. Oral cocaine-d? 2.0 mg/kg, intravenous cocaine-d? 1.0 mg/kg, and smoked cocaine-d? (200 mg) were administered after oral ethanol 1.0g/kg or placebo. A small, intravenous dose of deuterated cocaethylene (d?) also was administered with all conditions for determination of cocaethylene formation. Physiologic and subjective effects were recorded and plasma cocaine-d?, cocaethylene-d?, cocaethylene-d?, and benzoylecgonine-d? were measured by gas chromatography-mass spectrometry. About 24% (± 11) of intravenous cocaine was converted to cocaethylene. The oral route (34% ± 20) was significantly greater than from the smoked route (18% ± 11) and showed a trend toward significance for greater formation of cocaethylene compared to the intravenous route. Within each route, the cocaine-ethanol combination produced greater increases in heart rate and rate-pressure product than cocaine alone. Global intoxication effects across time after smoking or intravenous administration were significantly greater when cocaine and ethanol were both given. Administration of cocaine by different routes alters the amount of cocaethylene formed through hepatic first-pass effects. Increased cardiovascular and subjective effects might explain the toxicity and popularity of the combined drugs. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

First-pass metabolism of ethanol is predominantly gastric

Oral consumption of alcohol results in much lower blood alcohol concentrations (BACs) than does the same dose administered intravenously, suggesting significant first-pass metabolism (FPM). The questions remain, however, (1) whether this difference truly represents FPM or simply reflects slower absorption of alcohol, and (2) if there is FPM, is it mainly of gastric or hepatic origin. To study this, rats were given the same dose alcohol (1 g/kg) by either intragastric intubation or by intravenous, intraportal, and intraduodenal infusions at a rate that mimicked the loss of alcohol from the stomach. Higher BAC levels after intravenous than intragastric alcohol indicated true FPM. Higher levels after intraportal or intraduodenal infusions (in fact, comparable to those obtained with the intravenous route) demonstrated negligible FPM when the route of delivery bypassed the stomach, yet included the liver. Furthermore, rats that had developed portosystemic shunts after ligation of the portal ven exhibited blood alcohol curves and FPM equivalent to those of sham-operated controls, indicating that FPM is not dependent on first-pass flow through the liver, but reflects gastric metabolism. The absence of significant hepatic FPM is attributable to the saturation of hepatic alcohol dehydrogenase by recirculating alcohol, resulting in no appreciable increase in metabolism secondary to newly absorbed alcohol. Finally, the in vivo gastric metabolism of alcohol in pylorus-ligated rats was demonstrated by significantly lower BACs when alcohol was administered intragastrically than when an amount identical to that lost from the ligated stomach was given intraportally. Thus, the lower BACs with oral as opposed to intravenous alcohol are not simply a consequence of slow absorption, but result from FPM occurring predominantly in the stomach.     

Extrahepatic first-pass metabolism of nifedipine in the rat

The peroral (p.o.) bioavailability of nifedipine is reported to range from about 45 to 58% in the rat; this compares favourably to human beings. The metabolism of nifedipine is similar in rats and humans (oxidation of the dihydropyridine ring), with the liver believed to be solely responsible for the systemic clearance of the drug and the observed first-pass effect after p.o. dosing. The purpose of this study was to determine whether intestinal metabolism also contributes to the first-pass elimination of nifedipine in the rat. The systemic availabilities of nifedipine doses given by po, intracolonic (i.c.), and intraperitoneal (i.p.) routes of administration were compared to that for an intravenous (i.v.) dose (in each case a dose of 6 mg kg-1 was given) using adult male Sprague-Dawley rats (249-311 g, n = 6 or 7/group). The geometric mean of systemic nifedipine plasma clearance after i.v. dosing was 10.3 mL min-1 kg-1. The nifedipine blood-to-plasma ratio was found to be about 0.59. Therefore, the systemic blood clearance of nifedipine was about 17.5 mL min-1 kg-1; which, compared to the hepatic blood flow of rats (55 to 80 mL min-1 kg-1) showed that nifedipine is poorly extracted by the liver (0.22 < or = EH < = 0.32). The mean absolute bioavailabilities of the p.o., i.p., and i.c. doses were 61, 90, and 100%, respectively. Assuming complete absorption of the extravascular nifedipine doses these results indicate that, in addition to hepatic extraction, substantial first-pass elimination of nifedipine occurs within the wall of the small intestine but not the colon of the rat.     

Effect of ethanol and fructose on liver metabolism: a dynamic 31Phosphorus magnetic resonance spectroscopy study in normal volunteers

In vivo 31Phosphorus magnetic resonance spectroscopy (31P-MRS) permits evaluation of dynamic changes of individual phosphorus-containing metabolites in the liver parenchyma, such as phosphomonoester (PME), adenosine triphosphate, and inorganic phosphate (Pi). Intravenous fructose load alters phosphorus metabolites and allows assessment of liver function by 31P-MRS. 31P-MRS data obtained in alcoholic liver disease are however inconclusive. To study the hypothesis that fructose load can be used to investigate metabolic effects of ethanol ingestion, the interaction of different metabolites--i.e., fructose and ethanol--were followed in vivo. Using a 1.5 Tesla magnetic resonance system, six healthy volunteers were examined in three sessions each: a session after administration of (a) fructose only (250 mg/kg) was compared with (b) fructose load after ethanol ingestion (0.8 g/kg). A control experiment (c) was done after ethanol only. Spectra were acquired using one-dimensional chemical shift imaging with a temporal resolution of 5 min. Following a fructose load, the concomitant uptake of ethanol showed drastic changes of individual metabolic steps of the hepatic metabolism (averages +/- standard deviation). While the velocity of the net formation of PME (relative increase 0.46 +/- 0.11 without ethanol vs. 0.61 +/- 0.25 with ethanol) and the use of adenosine triphosphate (-0.13 +/- 0.03 vs. -0.16 +/- 0.03) and Pi (-0.022 +/- 0.009 vs. -0.021 +/- 0.004) were not significantly affected by ethanol uptake, a significant (p < 0.01) reduction of PME degradation (31.3 +/- 9.4 vs. 61.9 +/- 16.9 relative total area) and absence of an overshoot for Pi (10.5 +/- 4.9 vs. -7.1 +/- 5.3 relative area 13 min to 43 min) was observed after ethanol administration. Dynamic 31P-MRS allows the observation of individual steps of hepatic metabolism in situ; fructose metabolism in the human liver is slowed down by concomitant ethanol ingestion after the phosphorylation step of fructose. This could be explained by inhibition of aldolase rather than ethanol-induced changes of the hepatic redox state. Fructose load can be used to study effects of alcohol ingestion and might therefore be useful in patients with alcoholic liver disease.     

The vitamin B 6 requirements of the laying hen for reproduction

Some parameters related to withstanding severe cold (-20 degrees C) after administration of increasing doses of ethanol were investigated using guinea-pigs. The animals had been reared either at 22-23 degrees C or at 17-18 degrees C. They received ethanol in doses of 0.8 g, 1.2 g, 1.4 g or 1.6 g per kg of body weight. The fall of rectal temperature and its level at death were registered. The survival time, ethanol concentration in the blood and the brain, serum glucose and serum FFA at death were determined. In the animals reared at 22-23 degrees C the ethanol doses of 1.2-1.6 g/kg caused a significant shortening of the survival time and accelerated the fall of the rectal temperature. In addition the rectal temperature at death after ethanol was lower than in the controls. In the animals reared at 17-18 degrees C the ethanol doses used did not have any significant effect on the survival time and the rectal temperature. In both groups, ethanol concentration in the brain was lower (about 20-40%) than in the blood, the difference being greater in the group reared at 22-23 degrees C. Ethanol had no effect on the glucose concentrations. Serum FFA levels were slightly lower in animals reared at 22-23 degrees C than in those grown in the cooler temperature. It became evident that ethanol has a dose dependent deleterious effect on the thermoregulation of animals reared in warm (22-23 degrees C). The effect was seen at and above the dose of 1.2 g/kg. The results indicate further even a slight acclimation to cold was able to abolish the effect of these rather great doses of ethanol in severe cold exposure.     

Reassessment of glucose effectiveness and insulin sensitivity from minimal model analysis: a theoretical evaluation of the single-compartment glucose distribution assumption

Minimal model analysis with the frequently sampled intravenous glucose tolerance test provides an effective way to measure two important metabolic parameters in vivo under non-steady-state conditions: glucose effectiveness (SG) and insulin sensitivity (SI). Two questions regarding the validity of SG and SI have recently emerged. First, SG from the minimal model is suspected to be overestimated. Second, the occurrence of SI values indistinguishable from zero ("zero-SI") is not negligible in large clinical studies, and its physiological meaning is uncertain. In this study, we examined the significance of the assumed single-compartment glucose distribution embedded in the minimal model on the estimation of SG and SI. A more accurate two-compartment model was constructed by incorporating insulin action on hepatic glucose output and uptake into a previously validated construction. The two-compartment results were compared with the one-compartment minimal model results. It was shown that the one-compartment assumption contributes to a systematic deviation of SG (slope = 0.54, y-intercept = 0.014 min[-1]; n = 195 simulations). However, SG from the minimal model was linearly correlated to SG determined from the two-compartment model (r = 0.996). The one-compartment assumption also contributed to the occurrence of zero SI values for insulin-resistant subjects. A similar linear relationship was found between SI estimated by both the minimal model and the two-compartment model (slope = 0.58, y-intercept = -0.57 x 10[-4] min[-1] per pU/ml, r = 0.998). In conclusion, SG and SI from the minimal model are not necessarily equivalent to values emanating from the more accurate two-compartment model. However, the very high correlation between one- and two-compartment results suggests that the minimal model-derived SG and SI are dependable indexes of in vivo glucose effectiveness and insulin sensitivity. Minimal model analysis' advantages of simplicity, minimal invasiveness, reasonable reflection of non-steady-state glucose kinetics, and cost-effectiveness could in many cases outweigh the structural bias introduced by the model simplification.     

Balloon catheter systems for PTCA: the importance of the catheter length

This complex study was designed to measure the transport and excretion characteristics of gadolinium ethoxybenzyl diethylenetriaminepentacetic acid (Gd-EOB-DTPA) in dog's livers following bolus and infusion. Simultaneous T1 magnetic resonance imaging was performed to measure maximum signal enhancement. Anaesthetized dogs had cannulation of the common bile duct and urinary bladder for collections and cannulation of the femoral artery and vein for monitoring, blood sampling and infusion. Gd-EOB-DTPA was administered by bolus (range 12.5-200 mumol/kg) and infusion (range 0.4-6.4 mumol/min per kg). An hepatic transport maximum 0.09-0.15 mumol/min/kg was achieved with a blood concentration of 0.03-0.06 mumol/mL. Marked hepatic affinity for Gd-EOB-DTPA was demonstrated with measurements of liver concentration. Maximum T1 signal enhancement was achieved with blood Gd-EOB-DTPA concentration of 0.02-0.03 mumol/mL and a liver concentration of 1-2 mumol/g. The transport maximum for Gd-EOB-DTPA in the dog was similar to that for ipodate and iodipamide and effective imaging was achieved with sub-maximal doses. The maximum signal enhancement at blood concentrations less than required for maximum transport suggest a wide latitude for effective clinical imaging.     

Preferential reduction of first-pass elimination by ethanol. Model experiments with clomethiazole in the rabbit

The importance of the route of drug administration for drug ethanol interactions was studied using clomethiazole as model drug. To 10 rabbits equipped with permanently implanted catheters in the portal vein, the vena cava and the aorta respectively, clomethiazole was infused either into the portal vein or the vena cava and either together with i.v. saline or with i.v. ethanol. Arterial plasma clomethiazole and ethanol concentrations were measured by gas-liquid chromatography. After portal clomethiazole infusion, ethanol increased by the relative availability of clomethiazole to 270 +/- 90% (S.D.) of the saline controls, whereas after i.v. clomethiazole infusions the relative availability was increased only to 120 +/- 20% of the corresponding controls. Similarly, ethanol increased average plasma clomethiazole concentrations after 90 min of portal infusion from 5 to 14 nmol/ml, whereas after i.v. clomethiazole infusions the ethanol effect was small, the concentrations increasing only from 28 to 35 nmol/ml. These results are compatible with the concept that an ethanol-induced reduction of the hepatic capacity to metabolize a highly extracted drug is reflected to a much larger extent during first-pass elimination than during systemic clearance. Consequently, clinical toxicity in inebriated subjects is more likely to occur after oral than after parenteral administration of high extraction drugs.     

Stability measurement of oligonucleotides in serum samples using capillary electrophoresis

Five male subjects aged between 25 and 40 years were given methanol at a dose of 10 mg/kg, once orally and once intravenously, while the enzyme systems responsible for methanol oxidation were blocked by ethanol. The study assessed the duration of inhibition of methanol oxidation in relation to the blood ethanol concentration, and the elimination of methanol not influenced by ethanol. Methanol elimination was found to begin at a blood ethanol concentration of 0.04-0.13 g/kg. Elimination constants of 0.406-0.267 h-1 with corresponding half-lives of 1.71-2.60 h were established for methanol not influenced by ethanol. When data from a previous study using an identical protocol for parenteral administration were included, making the total number of subjects nine, the mean elimination constant was found to be 0.298 +/- 0.470 h-1 and the mean half-life 2.37 +/- 0.357 h, distribution being normal. No evidence of any differences in methanol elimination kinetics between alcoholics and non-alcoholics or of a significant influence of the route of administration was found. The extent of intraindividual variation in methanol elimination as indicated by the difference in each subject between the values established, expressed as a percentage of the corresponding mean values, was found to be 3-25%, which is comparable to the magnitude of intraindividual variation in the rate of ethanol elimination.     

Individual differences in the biphasic effects of ethanol

Ethanol exerts both stimulant-like and sedative-like subjective and behavioral effects in humans depending on the dose, the time after ingestion and, we will argue, also on the individual taking the drug. This study assessed stimulant-like and sedative-like subjective and behavioral effects of ethanol during the ascending and descending limbs of the blood alcohol curve across a range of doses in nonproblem social drinkers. Forty-nine healthy men and women, 21 to 35 years old, consumed a beverage containing placebo or ethanol (0.2, 0.4, or 0.8 g/kg) on four separate laboratory sessions, in randomized order and under double-blind conditions. Subjective and behavioral responses were assessed before and at regular intervals for 3 hr after ingestion of the beverage. The lowest dose of ethanol (0.2 g/kg) only produced negligible subjective effects compared to placebo. The moderate dose (0.4 g/kg) increased sedative-like effects 90 min after ethanol ingestion but did not increase ratings of stimulant effects at any time. The highest dose (0.8 g/kg) increased ratings of both stimulant- and sedative-like effects during the ascending limb and produced only sedative-like effects during the descending limb. Closer examination of the data revealed that individual differences in response to the highest dose of ethanol accounted for this unexpected pattern of results: about half of the subjects reported stimulant-like effects on the ascending limb and sedative-like effects on the descending limb after 0.8 g/kg ethanol, whereas the other half did not report stimulant-like effects at any time after administration of ethanol. These results challenge the simple assumption that ethanol has biphasic subjective effects across both dose and time, and extend previous findings demonstrating individual differences in response to ethanol.     

Obesity and high-density lipoprotein cholesterol in black and white 9- and 10-year-old girls: The National Heart, Lung, and Blood Institute Growth and Health Study

Acetaldehyde, the first metabolite of ethanol oxidation, has been proposed as a major initiating factor in ethanol-induced liver injury. The aims of this study were to examine whether acetaldehyde is absorbable from the digestive tract and whether, when delivered chronically in drinking water, it is capable of inducing liver injury in rats. Acetaldehyde concentrations in the rat portal and peripheral blood were measured by head space gas chromatography after intragastric (5 ml) and intracolonic (3 ml) administration of 20 mM acetaldehyde solution. In the hepatotoxicity study, rats were exposed to acetaldehyde (20 and 120 mM) delivered in drinking water for 11 weeks and histopathological changes in the liver were morphometrically assessed. Peak blood acetaldehyde levels were found at 5 min after acetaldehyde infusion and were 235 +/- 11 microM (mean +/- SE) after intragastric and 344 +/- 83 microM after intracolonic infusion of 20 mM acetaldehyde solution. The exposure of rats to 120 mM acetaldehyde solution for 11 weeks resulted in the development of fatty liver and inflammatory changes. Morphometric analysis showed significantly more fat accumulation in rats receiving 120 mM acetaldehyde solution (85 +/- 2 per cent of hepatocytes occupied by fat) than in rats receiving 20 mM acetaldehyde solution (38 +/- 11 per cent) or in controls (36 +/- 10 per cent). The dose of extrahepatic acetaldehyde (500 mg/kg per day) producing liver injury corresponds to only around 3 per cent of that derived from hepatic ethanol oxidation in animals receiving an ethanol-containing totally liquid diet (15 g/kg per day). These results indicate that acetaldehyde delivered via the digestive tract can reach the liver by the portal circulation and that acetaldehyde of extrahepatic origin appears to be more hepatotoxic than acetaldehyde formed during ethanol oxidation within the liver.     

Application of a first-pass effect model to characterize the pharmacokinetic disposition of venlafaxine after oral administration to human subjects

Venlafaxine (VEN), a drug used in the treatment of depression, undergoes significant first-pass metabolism after oral dosing to O-desmethylvenlafaxine (ODV), a metabolite with comparable therapeutic activity to that of parent drug. The pharmacokinetic disposition of VEN was characterized using a "first-pass" model that incorporates a presystemic compartment (liver) to account for the first-pass metabolism of VEN to ODV. A series of differential equations were simultaneously fitted to plasma concentrations of parent and metabolite. A good fit of the model to observed data was demonstrated, generating estimates for the following parameters: ka (1.31 +/- 0.009 hr-1), VVEN (252 +/- 87.6 liters), CLint (65.8 +/- 39.7 liters/hr), RL (liver:plasma partition coefficient, 29.6 +/- 18. 3), VODV (181 +/- 84.1 liters), and CLODV (23.5 +/- 12.5 liters/hr). Parameter estimates correlated closely with those obtained through noncompartmental methods. These results indicate that the time-course disposition of a compound undergoing first-pass hepatic metabolism after oral dosing can be successfully modeled.