Estimation of the amount of alcohol ingested from a single blood alcohol concentration.

Capillary blood alcohol concentrations (BAL) measured in 22 young adult male volunteers each of whom received three different treatments of alcohol (total N = 66) have been related quantitatively to the dose of alcohol ingested. Linear regression with reasonably homogeneous variances have been found when the BAL at 2, 2.5 and 3 hr are divided by the person's body weight and plotted versus the g/kg (D/W) dose. Error analysis indicated that the least error in the predicted dose (D/W) was obtained for BAL measured at 2 hr post dosing. In the latter case the mean absolute error was 6.23%, 59% of the errors were within +/- 5% and 88% of the errors were within +/- 10%.

Parameters Vm' and Km for elimination of alcohol in young male subjects following low doses of alcohol.

Seventy-four (44 under fasting conditions and 30 following oral liquid meals) sets of post-absorptive human capillary blood alcohol concentration-time data were computer-fitted to the integrated form of the Michaelis-Menten equation by numerical integration by nonlinear least squares to provide 74 pairs of the kinetic Vm' and Km parameter values. The parameters were highly correlated (r = 0.915) by orthogonal least squares. Eight of the fasting subjects received four different oral doses of alcohol and fourteen subjects each received three different alcohol treatments. Intra-subject variances of Vm', Km and the ratio Vm' Km were calculated from the multiple treatments. Inter-subject variances were calculated from the 22 mean values of each parameter. Each parameter and the intra-subject variances of the parameters were found to be log normally distributed. The liquid meals (carbohydrate, fat and protein separately) appeared not to affect the parameter values. The computer fittings were all excellent as evidenced by the relatively small standard deviations of the estimated parameters and other statistical measures of fit.

Pharmacokinetics of ivermectin administered intravenously to cattle.

Ivermectin, a macrocyclic lactone disaccharide antiparasitic agent, was administered intravenously to six young calves (one bull, five steers) as a bolus dose of 200 micrograms/kg. The disposition kinetics of ivermectin in cattle can be described by a three-compartment open model with elimination from the central compartment. Compartmental analysis yielded mean parameters as follows: terminal elimination rate constant (beta) = 0.258 d-1, biological half-life (t 1/2 beta) = 2.7 d; apparent volume of distribution of the central compartment (Vd1) = 0.45 L/kg; apparent volume of distribution at steady state (Vdss) = 2.4 L/kg. The area under the plasma concentration-time curve (AUC) was 254 ng X d/mL. Noncompartmental parameters, obtained by utilizing statistical moment theory, mean residence time (MRT), clearance (CL), and Vdss were calculated to be 2.8 d, 0.79 L/kg X d, and 2.2 L/kg, respectively.

Oral controlled-release delivery of ivermectin in cattle via an osmotic pump.

Ivermectin, a potent antiparasitic agent with activity against internal and external parasites, was delivered to cattle at a controlled zero-order rate for 35 d via orally administered, specially weighted, ALZET 2ML4 osmotic pumps. The osmotic pumps delivered the drug consistently over the trial period. Steady-state levels in plasma were achieved in 7-14 d, and plasma concentration depletion curves were observed to start at approximately day 35, the theoretical delivery lifetime of the osmotic pumps. Bioavailability was estimated to be 40%, and dose rate-plasma steady-state interrelationships were shown to be linear.

Surgical catheterization of heptic-portal and peripheral circulations and maintenance in pharmacokinetic studies.

A surgical procedure for the chronic catheterization of mongrel dogs was presented with a detailed account of the use and maintenance of these catheters. The methodology allowed for a direct determination of the capacity of the liver to the intact animal to metabolize drugs. The technique permitted the investigator to study the oxidation of drugs by the liver in a specific concentration range and assessment of the first-pass effect of the liver when many drugs are administered via the oral route. The dogs were prepared and use in the drug pharmacokinetic studies for periods up to 24 days.

A new blood-flow pharmacokinetic model for ethanol.

A multicompartmental mathematical model, taking into account observed vascular concentration gradients and blood flow rate limitations, has been proposed. Based on blood flows and blood and tissue volumes reported in the literature and in personal communications, an appropriate model was elaborated for ethanol in the dog. The relatively high values of r2 and a correlation coefficient determined for the simultaneous computer fitting of mean observed blood ethanol concentration, time data from two administered doses, support the proposed model. While the surgery is prohibitive for human experimentation, correlations may be extended to man. The elaboration of a more complete multicompartmental model for ethanol should prove beneficial in revealing the relationships among the doses of alcohol, the circulating blood ethanol concentrations, and physiological and psychomotor test parameters.

Arterial-venous blood alcohol concentration gradients.

Arterial and venous blood alcohol concentration (BAC)-time courses were completely defined in the peripheral circulations, both during and after the constant rate infusions of ethanol via the cephalic vein or hepatic artery in the dog. These BAC data were characterized by the following trends. (1) A much faster rise in the blood alcohol curve, as well as a higher peak BAC was found using the shorter infusion time. (2) During infusion, the alcohol concentration was higher in arterial or arterialized blood than venous blood when infusion was via the cephalic vein. (3) Peak BAC was higher in the femoral artery than the femoral vein whether infusion was via the cephalic vein or hepatic artery. (4) Peak BAC was higher in the hepatic artery or portal vein than the hepatic vein when infusion was via the cephalic vein. When administration was directly into the liver, the peak BAC in the hepatic vein was higher than the portal vein. (5) After infusion ceased, there was an arterial-venous inversion; peripheral arterial ethanol concentrations were significantly less (p less than 0.001) than corresponding venous concentrations; with cephalic vein administration, a hepatic vein-portal crossover was observed, the reverse being true when ethanol was administered via the hepatic artery. In either case, the BAC was observed to be higher in the hepatic artery than the portal vein or hepatic vein throughout the sampling period. (6) BAC was observed to be higher for the same sampling times at the respective sites when ethanol was administered directly into the liver. While the methodology in this study is prohibitive for human experimentation, correlations may be extended to man. The elaboration of the arterial-venous concentration differences for ethanol should prove beneficial in revealing the relationships among the doses of alcohol, the circulating blood ethanol concentrations, and physiological and psychomotor test parameters in man.

Nonlinear pharmacokinetics of ethanol: the disproportionate AUC-dose relationship.

Whole venous blood concentrations of ethyl alcohol were measured following the constant rate intravenous infusion of ethanol to four Beagle dogs. Five different doses (0.1-0.8 g ethanol/kg body weight) were administered at scheduled intervals. The area under the blood ethanol concentration-time curves (AUC) was found to demonstrate a markedly nonlinear relationship with the administered dose. Simulations of one and two compartment open models with Michaelis-Menten elimination kinetics and zero-order input are presented with their theoretical AUC-dose relationships.

Pharmacokinetics of ethanol: a review.

The pharmacokinetics of ethanol in man are reviewed from a historical perspective from the earliest attempts at kinetic analysis of urinary data in 1899 to the present nonlinear analysis of blood alcohol concentration (BAC) and time data. Review of the various kinetic theories that have been utilized to describe the kinetics of alcohol metabolism is provided. Extensive review is made of recent investigations supporting the application of Michaelis-Menten enzyme kinetics to describe alcohol metabolism. Results of direct, nonlinear least-squares computer fitting of BAC following intravenous and oral feeding of alcohol both in the fasting and fed states are presented with appropriate theory. The kinetics of the oral absorption of alcohol and the relationship among stomach emptying rate, the apparent absorption rate, and the area under the BAC-time curve are discussed and data presented. The kinetics of multiple Michaelis-Menten pathways are discussed with application to the (potential) contributions of the MEOS and/or ADH systems to the observed BAC curve and resultant kinetic parameters. Several methods of obtaining pharmacokinetic (Michaelis-Menten) parameters from BAC curves and their interpretation and usage in comparative studies are presented.

Food effects on absorption and metabolism of alcohol.

The concomitant ingestion of various foods with alcohol resulted in a decreased area under the blood alcohol concentration curve, a lower peak concentration and an increased time to reach peak. Michaelis-Menten kinetics indicated a decreased alcohol metabolism rate after the ingestion of carbohydrates or fats.

Concentrations of ethanol in two segments of the vascular system.

The time courses of capillary and venous blood concentrations of ethanol after oral administration of 0.30 and 0.34 g/kg doses of ethanol to two normal human subjects indicated that, by interpolation, equal capillary and venous concentrations are reached at only one time, and this time varied with the subject. The capillary/venous blood concentration ratios varied markedly as a function of time in both subjects over the entire observation period of 4 h.

Blood ethanol concentrations during and following constant-rate intravenous infusion of alcohol.

Blood ethanol concentrations were determined in 7 subjects during and subsequent to a 2-hr constant-rate intravenous infusion of ethyl alcohol (8% v/v). Eight to 10 capillary blood samples were collected during the infusion and 10 to 21 samples were obtained after the infusion ceased. Thus, the total time course of blood ethanol concentrations in man was defined, both during and postinfusion. Blood ethanol concentration data from each of 6 subjects were fitted simultaneously to the two equations for the one-compartment open model with zero order input and Michaelis-Menten elimination kinetics. The average Vm[0.232 mg/(ml x hr)] and Km[0.0821 mg/ml] obtained fron these fittings correspond very closely with corresponding values estimated by the fitting of all the mean concentration-time data obtained following oral administration of 4 different doses of ethanol to 8 other fasting subjects in another study. A disproportionate increase in area under the concentration-time curve with increase in dose (gm/kg) was observed in a single subject who was infused with equal volumes of a 4% and an 8% (v/v) ethanol solution at the same constant rate.