Cimetidine-methylprednisolone-theophylline metabolic interaction.

The pharmacokinetics of theophylline and methylprednisolone were examined before and during cimetidine treatment in an asthmatic woman who required long-term administration of these drugs. Cimetidine reduced theophylline plasma clearance by 30 percent, and measurement of urinary metabolites showed that 3-methylxanthine formation was inhibited more strongly than that of the methylated uric acid metabolites. Assessment of methylprednisolone disposition following oral and intravenous doses revealed no effect of cimetidine on the bioavailability (74 to 81 percent absorption) or plasma clearance (22 to 24 liters per hour) of the steroid. Thus, cimetidine exhibits variable and selective effects on the biotransformation pathways of drugs important in asthma therapy.

No effect of age on the dose requirement of thiopental in the rat.

With increasing human age (20-80 years), the electroencephalogram (EEG) dose requirement for the intravenous anesthetic thiopental decreases approximately 10% per decade of life. The goal of this study was to compare the dose required to attain isoelectric EEG in young (4-5 month) vs. aged (24-25-month) Fischer 344 rats. One second isoelectricity was found to be an endpoint where minimal cardiorespiratory depression occurred. The effects of age, infusion rate, and repeated administration were examined in nine young and nine old rodents. Thiopental dose requirement increased with increasing infusion rates. Repeated administration at two-day intervals did not demonstrate tolerance to thiopental. No difference in thiopental dose requirement was detected in the young vs. elderly rats. In a separate group of five young and five old rats, thiopental plasma, brain, heart, and CSF concentrations were measured when five seconds of EEG isoelectricity was achieved: no consistent differences were noted. The rat may not be an appropriate model to investigate acute age-related anesthetic effects in humans, because cardiovascular changes with age are dissimilar between species.

Parameter estimability of biphasic response models.

Pharmacodynamics of general anesthetic agents generally exhibit biphasic concentration-effect relationships (i.e., an activation phase at low concentrations and inhibition at higher concentrations). These relationships are usually characterized with biphasic models constructed from various combinations and modifications of the nonlinear sigmoid E(MAX) model. We tested and quantified the parameter estimability of the simplest additive biphasic pharmacodynamic models by a Monte Carlo method. The estimated model parameters were used to calculate descriptors of the concentration-effect data. Parameters and descriptors were compared with their true values. When the IC50/EC50 ratio was low (<10), E(MAX), EC50, and IC50 were poorly estimated (high coefficient of variation and pronounced bias). However, the fit to the data was excellent, and the data descriptors calculated from the estimated model parameters demonstrated high precision and accuracy. Baseline effect (E0) was estimated with good precision and accuracy. As the IC50/EC50 ratio was increased, the estimability of model parameters and data descriptors improved, with the data descriptors continuing to be more estimable than model parameters. Thus, model parameters become estimable when there is sufficient separation between EC50 and IC50 to produce a plateauing of peak effect (activation), which can be observed directly from the data signature. Data descriptors are not subject to this limitation and thus may serve as better metrics for summarizing concentration-effect relationships.

Precursor-dependent indirect pharmacodynamic response model for tolerance and rebound phenomena.

A precursor-dependent model of indirect pharmacodynamic response which can describe tolerance and rebound was characterized in terms of the effects of changes in the fundamental properties of the drug on its response profiles. The model extends previous models by considering inhibition or stimulation of production of the response variable dependent on the amount of precursor which may accumulate or deplete after administration of some drugs. Standardized pharmacokinetic and pharmacodynamic parameters were used for generating dose, plasma concentration, and response-time profiles using computer simulations. The peak response (Rmax) and the time of its occurrence (TRmax) were dependent on the dose, degree of maximum inhibition (Imax) or stimulation (Smax), and drug concentrations causing 50% inhibition (IC50) or stimulation (SC50). The maximum rebound (RBmax) and the time of its occurrence (TRBmax) after a single bolus dose were also dependent on these factors, but were of lesser magnitude and showed relatively later occurrence. Interestingly, values of area between the baseline and effect curve (ABEC) and area between the baseline and rebound curve (ABRC) were equal for each set of conditions for each model, but the latter is reduced when there is a second pathway for loss of precursor. Tolerance occurs because of diverse mechanisms, and the response patterns demonstrated may be helpful in describing tolerance and rebound phenomena for drugs which affect precursor pools.

Is it possible to estimate the parameters of the sigmoid Emax model with truncated data typical of clinical studies?

Many drug concentration-effect relationships are described by the nonlinear sigmoid E(max) model. Clinical considerations frequently limit the magnitude of effect intensity that may be produced; the most pronounced effect intensity may be considerably below E(max). We have tested and quantified the influence of this limitation on the estimatability of the sigmoid E(max) model parameters. We have used the estimated parameter values to calculate data descriptors (drug concentrations required to produce certain effect intensities) and compared these with concentrations determined by using exact parameter values. We found that when the highest measured effect intensity was less than 95% of E(max), E(max) and EC50 were poorly estimated (high coefficient of variation and pronounced bias). Nevertheless, the fit to the data was quite good and the data descriptors were estimated with precision within the range for which data were available but not beyond. Baseline effect was estimated with good precision but the sigmoidicity parameter (gamma) was highly variable. Thus, where clinical considerations prevent determination of concentration-effect data near the maximum effect intensity, E(max) and EC50 estimations are unreliable. The use of estimable data descriptors is proposed to characterize the concentration-effect relationship under these conditions.

Concentration-EEG effect relationship of propofol in rats.

Propofol is a unique highly lipid-soluble anesthetic that is formulated in a fat emulsion (Diprivan) for intravenous (i.v.) use. It has the desirable properties of rapid onset and offset of effect following rapid i.v. administration and minimal accumulation on long-term administration. Based on physicochemical properties and preliminary brain solubility data, propofol should have an extended effect-site turnover and a resulting prolonged effect. However, a preliminary study in humans has reported a rapid blood-brain equilibration half-time (T1/2 kE0) of only 2.9 min. We used a chronically instrumented rat model to examine the unique disposition and electroencephalographic (EEG) pharmacodynamics of propofol. Although the pharmacokinetics were variable, there was low interindividual variability in the concentration-EEG effect relationship. The duration of EEG sleep was 26 (+/- 44% CV) min following 11-15 mg/kg doses of propofol. The T1/2 kE0 was 1.7 (+/- 32%) min. Apparent effect-site concentrations of 0.5-1 microg/mL were required to maintain sleep in rats. Like other general anesthetics, the concentration-EEG effect relationship of propofol is biphasic. At a propofol concentration of 0.6 (+/- 35%) microg/mL, the number of EEG waves/s was maximal at 175% of baseline awake state. Further increases in the concentration of propofol depressed EEG activity until complete suppression occurred at 7 (+/- 22%) microg/mL.

6 alpha-Methylprednisolone and 6 alpha-methylprednisone plasma protein binding in humans and rabbits.

The binding of 6 alpha-methylprednisolone and 6 alpha-methylprednisone to proteins of rabbit and human plasma was studied in vitro by equilibrium dialysis. Steroid binding was determined using radiolabeled compounds and HPLC analysis methods. Both methods produced equivalent results. Plasma protein binding of 6 alpha-methylprednisolone and 6 alpha-methylprednisone averaged 75-82% and was independent of steroid concentration, suggestive of low affinity, nonspecific protein binding. A positive linear correlation of the log octanol-water partition coefficient with the nonspecific binding affinities of a homologous series of steroids, including 6 alpha-methylprednisolone and 6 alpha-methylprednisone, was demonstrated. This correlation suggests that hydrophobic binding is a major determinant of nonspecific steroid-protein interactions.

Chlorothiazide absorption from solution and tablet dosage forms in dogs.

The bioavailability of an aqueous solution of chlorothiazide and three commercially available chlorothiazide tablets was assessed in adult mongrel dogs. In two crossover urinary excretion studies, six fasting dogs received single 500-mg doses of chlorothiazide as an aqueous solution, one 500-mg originator tablet on two separate occasions (Tablets A-1 and A-2), two 250-mg originator tablets (Tablet B), or one 500-mg generic tablet (Tablet C). 6-Amino-4-chlorobenzene-1,3-disulfonamide )chloraminophenamide), a pharmacologically active hydrolysis product of chlorothiazide was not detected in any urine sample. Urinary recoveries of chlorothiazide after oral administration, expressed as the mean (range) percent of the dose, was only 22.0 (8.41-33.9), 15.7 (10.2-25.0), 20.7 (7.25-31.0), 18.5 (8.72-33.2), and 21.9% (6.69-41.1%) for the aqueous solution and Tablets A-1, A-2, B, and C, respectively. Considerable interindividual variation and some intraindividual variation were observed. No statistically significant difference in bioavailability existed among the aqueous solution and Tablets A-2 and B, between Tablets A-1 and C, and between Tablets A-1 and A-2.

Formulation-dependent pharmacokinetics and pharmacodynamics of propofol in rats.

Propofol, a highly lipophilic anaesthetic, is commercially formulated as a lipid emulsion (diprivan) for intravenous use. This formulation is characterized by rapid onset and offset of effect after rapid intravenous administration and an effect-site equilibration half-life (t1/2kE0) of 1.7 min in rats. Paradoxically these characteristics are usually associated with relatively water-soluble anaesthetics. To test the influence of the formulation on propofol pharmacokinetics, effect-site equilibration kinetics and pharmacodynamics we performed a pharmacokinetic-pharmacodynamic study of propofol in chronically instrumented rats after administration in a lipid-free formulation. In this report we present the results of this study and compare these results with previous data obtained with rats receiving propofol in the emulsion formulation. Compared with the emulsion formulation the distribution volumes (VdC and VdSS) were significantly higher but the t1/2kE0 (2.0 min) was similar for the lipid-free formulation. The concentration-effect relationship was biphasic. Propofol effect-site concentrations required to achieve 50% activation, peak activation, 50% inhibition of peak activation effect and maximum inhibition were significantly lower, indicating a higher apparent steady-state potency for the lipid-free formulation compared with the emulsion formulation. The evanescent characteristics of propofol's effect-time-course disappeared when the anaesthetic was administered in the lipid-free formulation. These results suggest that the nature of the formulation can profoundly influence the clinical characteristics of intravenously administered drugs by modifying the pharmacokinetics or pharmacodynamics or both.

A PC-based graphical simulator for physiological pharmacokinetic models.

Since many intravenous anesthetic drugs alter blood flows, physiologically-based pharmacokinetic models describing drug disposition may be time-varying. Using the commercially available programming software MATLAB, a platform to simulate time-varying physiological pharmacokinetic models was developed. The platform is based upon a library of pharmacokinetic blocks which mimic physiological structure. The blocks can be linked together flexibly to form models for different drugs. Because of MATLAB's additional numerical capabilities (e.g. non-linear optimization), the platform provides a complete graphical microcomputer-based tool for physiologic pharmacokinetic modeling.

Troleandomycin effects on methylprednisolone and methylprednisone interconversion and disposition in the rabbit.

A study of the effects of troleandomycin (TAO) on the disposition of intravenous methylprednisolone in rabbits was performed in order to develop an animal model to further evaluate the mechanism of TAO/steroid beneficial effects in severe asthma. The plasma concentration-time profiles of methylprednisolone and methylprednisone were determined in the presence and absence of single and multiple dose TAO regimens. Pharmacokinetic analysis revealed a significant decrease in total plasma clearance of methylprednisolone in the presence of multiple dose TAO. Alterations in the disposition of the reversible metabolite, methylprednisone, were also observed. The TAO-methylprednisolone interaction may involve decreasing the degree of interconversion between the steroid and its reversible metabolite. TAO also decreases metabolite turnover more than three-fold. The antibiotic does not cause marked deviation from linear biexponential elimination of methylprednisolone as observed in man. The rabbit may serve as a useful animal model for further studies of the TAO/methylprednisolone interaction.

Population pharmacodynamics: strategies for concentration-and effect-controlled clinical trials.

OBJECTIVE: To explore and evaluate various strategies for drug concentration-and effect-controlled clinical trials, respectively, in the context of studies of population pharmacodynamics (concentration-effect relationships). METHODS: The relative utility of drug concentration- and pharmacologic effect-controlled, randomized clinical trials with two or three concentration-effect measurements for each subject has been explored by computer simulation. The basis for these simulations was a sigmoid-Emax (maximum effect) pharmacodynamic model with Emax = 100%, EC50 (drug concentrations required to produce an effective intensity of 50%) = 10 concentration units, gamma = 2, and no hysteresis. Emax and gamma were held constant whereas EC50 was assumed to be log-normally distributed with a 26% coefficient of variation of the natural lognormalized data. A smaller random variability and variability due to measurement error also were incorporated in the simulations. To explore the implications of variable and unknown Emax and gamma values, the suitability of linear and log-linear interpolation procedures for two-point concentration-effect data in different regions of the sigmoid-Emax curve was compared. RESULTS: Pharmacologic effect-controlled clinical trials with 300 hypothetical subjects and targeted effect intensities of 25% and 75% yielded very good estimates of drug concentrations required to produce effect intensities of 35%, 50%, and 65%, whereas concentration-controlled trials yielded much poorer estimates. Moreover, the concentration-controlled trials, despite optimum choice of targeted concentrations, yielded a large number of data points with poor information content (effect intensities of < 15% or > 85%). Determinations based on targeted effect intensities of 25% and 75% yielded better estimates of individual EC50 values than those targeted for 25% and 50% or 50% and 75% effect intensity. Results were not significantly improved by adding a third measurement (targeted to 50% effect) to the 25% and 75% effect design. Estimations of drug concentrations required to produce an effect intensity of 50%, based on log-linear interpolation of exact concentration-effect data at 25% and 75%, yielded exact results independent of gamma value (0.5-8.0) whereas linear interpolation produced large overestimates at gamma = 0.5 or 1.0 but satisfactory estimates at gamma > or = 2.0. Similar calculations for an effect intensity of 15% based on exact concentration-effect data at 5% and 25% yielded reasonably good estimates by both methods of interpolation over a wide range of gamma values. A review of the clinical literature showed that gamma values are usually 2 or higher. CONCLUSIONS: Population pharmacodynamic studies of reversibly acting drugs without pharmacodynamic hysteresis or time dependency (e.g., tolerance) can be successfully conducted using a pharmacologic effect-controlled randomized clinical trial design with only two properly selected target effect intensities per subject.

Emulsion formulation reduces propofol's dose requirements and enhances safety.

BACKGROUND: Propofol, a highly lipophilic anesthetic, is formulated in a lipid emulsion for intravenous use. Propofol has brisk onset and offset of effect after rapid administration and retains rapid offset characteristics after long-term administration. The authors tried to determine whether the emulsion vehicle is requisite for propofol's evanescent effect-time profile. METHODS: The time course of sedation and electroencephalographic (EEG) effect after propofol administration was measured in three studies in rats instrumented. In study 1, propofol was infused in either emulsion or lipid-free vehicle (n = 12), in a repeated measures cross-over design. In study 2, propofol in lipid-free vehicle was infused with or without simultaneous infusion of drug-free lipid emulsion (n = 6) in a repeated measures cross-over design. In study 3, propofol was infused in either emulsion (n = 5) or lipid-free vehicle (n = 5) to EEG burst suppression. RESULTS: In study 1, relative to the emulsion formulation, propofol administered at equivalent doses in lipid-free vehicle resulted in a longer time to effect onset (1.4 +/- 0.2 vs. 0.5 +/- 0.1 min, EEG) and a trend for delayed anesthetic recovery (26.8 +/- 9.4 vs. 17 +/- 3.5 min, EEG; 26.1 +/- 8.8 vs. 16.8 +/- 3.3 min, sleep). In study 2, coadministration of drug-free emulsion with propofol did not alter the time course of effect. In study 3, more than twice the dose of propofol was required to achieve EEG burst suppression with the lipid-free formulation. Two animals died after administration of propofol to EEG burst suppression with the lipid-free formulation; no deaths occurred in the emulsion group. CONCLUSION: The incorporation of propofol in emulsion reduces dose requirements and produces rapid onset and recovery of anesthetic effect.

The determination of essential clearance, volume, and residence time parameters of recirculating metabolic systems: the reversible metabolism of methylprednisolone and methylprednisone in rabbits.

Methods based on moment analysis are described which permit the calculation of the fundamental parameters of reversible drug/metabolite systems. These parameters include the four essential clearances of reversible and irreversible elimination, the central and steady-state distributional volumes, and the sojourn times or turnover rates of the metabolic pair. Additional parameters unique to interconversion systems are developed which describe the properties of metabolic entrapment ("recycled fraction"), conservation ("exposure enhancement"), and equilibrium resulting from reversible metabolism ("Percent parent drug at steady-state"). Parameters obtained by these methods are compared to those generated by conventional mammillary analysis. The influence of perturbation of essential parameters on the response of mammillary descriptors and the state of the interconversion system are simulated. The interconversion analysis is applied to disposition data for methylprednisolone and methylprednisone in the rabbit. Mammillary methods underestimate the metabolic clearance of these two steroids by 30%, while steroid turnover is underestimated by 100%. The steady-state volumes of distribution of the two steroids are overestimated by 10 and 61%. Additional literature data for disposition of several corticosteroids in various species and disease states are reanalyzed. Examination of cortisol/cortisone disposition in thyroid disorders reveals that mammillary methods detect the overall acceleration of steroid elimination in hyperthyroidism, but fail to reveal a 50% reduction in metabolite backconversion and decreased metabolic cycling. These moment analysis methods should facilitate characterization of the pharmacokinetics of the increasing array of reversible drug/metabolite systems.

Formulation-dependent brain and lung distribution kinetics of propofol in rats.

BACKGROUND: Propofol when administered by brief infusion in a lipid-free formulation has a slower onset, prolonged offset and greater potency compared with an emulsion formulation. To understand these findings the authors examined propofol brain and lung distribution kinetics in rats. METHODS: Rats were infused with equieffective doses of propofol in emulsion (n = 21) or lipid-free formulation (n = 21). Animals were sacrificed at various times to harvest brain and lung. Arterial blood was sampled repeatedly from each animal until sacrifice. Deconvolution and moment analysis were used to calculate the half-life for propofol brain turnover (BT) and brain:plasma partition coefficient (Kp). Lung concentration-time profiles were compared for the two formulations. RESULTS: Peak propofol plasma concentrations for the lipid-free formulation were 50% of that observed for emulsion formulation, whereas peak lung concentrations for lipid-free formulation were 300-fold higher than emulsion formulation. Brain Kp calculated from tissue disposition curve and ratio of brain:plasma area under the curves were 8.8 and 13, and 7.2 and 9.1 for emulsion and lipid-free formulations, respectively. BT were 2.4 and 2.5 min for emulsion and lipid-free formulations, respectively. CONCLUSIONS: Significant pulmonary sequestration and slow release of propofol into arterial circulation when administered in lipid-free vehicle accounts for the lower peak arterial concentration and sluggish arterial kinetics relative to that observed with the emulsion formulation. Higher Kp for the lipid-free formulation could explain the higher potency associated with this formulation. BT were independent of formulation and correlated with values reported for effect-site equilibration half-time consistent with a distribution mechanism for pharmacologic hysteresis.

Pharmacodynamic characterization of the electroencephalographic effects of thiopental in rats.

We have developed a chronically instrumented rat model that uses changes in electroencephalographic wave forms to estimate continuously the degree of central nervous system (CNS) depression induced by thiopental. Such changes were subject to aperiodic signal analysis, a technique that breaks down the complex EEG into a series of discreet neurologic "events" which are then quantitated as waves/sec. We thus obtained a continuous measure of CNS drug effect. In addition we continuously recorded central arterial blood pressure and heart rate and monitored ventilatory status using arterial blood gas determinations. We also determined, with frequent arterial blood sampling, the distribution and elimination of thiopental in individual animals. The time lag occurring in the curve representing arterial concentration of thiopental vs. EEG effect suggests that arterial plasma is not kinetically equivalent to the EEG effect site. Application of semiparametric pharmacodynamic modeling techniques enabled us to estimate equilibration rate constant (Keo) for concentrations of thiopental between arterial plasma and the effect site. The half-life for equilibration of thiopental with the EEG (CNS) effect was less than 80 sec. Knowledge of the rate of equilibration permitted characterization of the relationship between the steady state plasma concentrations and CNS effect of thiopental, as measured by activation and slowing of the EEG. At concentrations of thiopental below 5 micrograms/ml, EEG activity was 180% higher than during the baseline awake state. Thiopental produced an activated EEG over more than 20% of the concentration-effect relationship. Further increases in the concentration of thiopental at the site of effect depressed EEG activity progressively until complete suppression of the EEG signal occurred (at which time, the concentration was approximately 80 micrograms/ml). This report describes our model and its application to the assessment of the pharmacodynamics of thiopental as manifested by changes on the EEG.

From piecewise to full physiologic pharmacokinetic modeling: applied to thiopental disposition in the rat.

Physiologically based pharmacokinetic modeling procedures employ anatomical tissue weight, blood flow, and steady tissue/blood partition data, often obtained from different sources, to construct a system of differential equations that predict blood and tissue concentrations. Because the system of equations and the number of variables optimized is considerable, physiologic modeling frequently remains a simulation activity where fits to the data are adjusted by eye rather than with a computer-driven optimization algorithm. We propose a new approach to physiological modeling in which we characterize drug disposition in each tissue separately using constrained numerical deconvolution. This technique takes advantage of the fact that the drug concentration time course, CT(t), in a given tissue can be described as the convolution of an input function with the unit disposition function (UDFT) of the drug in the tissue, (i.e., CT(t) = (Ca(t)QT)*UDFT(t) where Ca(t) is the arterial concentration, Q tau is the tissue blood flow and * is the convolution operator). The obtained tissue until disposition function (UDF) for each tissue describes the theoretical disposition of a unit amount of drug infected into the tissue in the absence of recirculation. From the UDF, a parametric model for the intratissue disposition of each tissue can be postulated. Using as input the product of arterial concentration and blood flow, this submodel is fit separately utilizing standard nonlinear regression programs. In a separate step, the entire body is characterized by reassembly of the individuals submodels. Unlike classical physiologic modeling the fit for a given tissue is not dependent on the estimates obtained for other tissues in the model. Additionally, because this method permits examination of individual UDFs, appropriate submodel selection is driven by relevant information. This paper reports our experience with a piecewise modeling approach for thiopental disposition in the rat.

Feasibility of effect-controlled clinical trials of drugs with pharmacodynamic hysteresis using sparse data.

PURPOSE: To explore, by simulation procedures, the feasibility of characterizing, from sparse data, the concentration-effect relationship of drugs with pharmacodynamic hysteresis. METHODS: For computer simulations, the concentration-effect relationship was assumed to be describable by the Sigmoid-Emax equation, the site of drug action was located in a distinct effect compartment (keo = 10 x kelim), and the pharmacokinetics were those of either a linear one- or two-compartment system. In view of the poor estimability of the parameters of the Sigmoid-Emax model under the usual clinical conditions, central compartment post-distributive drug concentrations required to elicit various intensities of effect within the therapeutic range were used as data descriptors. Effect intensities of 5 and 25, or 25 and 50 units (with the "unknown" Emax = 100 units) were targeted in multiple-dose (steady state) trial designs. From these data, drug concentrations required to produce effect intensities of 15 and 50 units were estimated by both log-linear and linear interpolation and the actual effect intensities produced by these concentrations were calculated. These simulations were performed over a wide range of Hill coefficient values (0.5 to 4.0) and dosing intervals (0.1 to 1.5 x elimination t1/2. RESULTS: Acceptable results could be obtained by measuring drug concentrations and effect intensities at or near the end of a dosing interval. The largest deviations of effective concentration estimates (in terms of effect intensity) occurred at a Hill coefficient value of 0.5 and the results were very little affected by changing the dosing interval. CONCLUSIONS: Our results demonstrate that effect-controlled clinical trials, with sparse data, of drugs with pharmacodynamic hysteresis for determining concentration-effect relationship in the therapeutic range are feasible in principle.