Development of a physiologically based pharmacokinetic model of isopropanol and its metabolite acetone.

A physiologically based pharmacokinetic (PBPK) model for isopropanol (IPA) and its major metabolite, acetone, is described. The structure of the parent chemical model, which can be used for either IPA or acetone by choosing the appropriate chemical-specific parameters, is similar to previously published models of volatile organic chemicals such as styrene. However, in order to properly simulate data on the exhalation of IPA and acetone during inhalation exposures, it was necessary to expand the description of the lung compartment to include a subcompartment for the upper respiratory tract mucus layer. This elaboration is consistent with published PBPK models of other water-soluble vapors in which the mucus layer serves to absorb the chemical during inhalation and then release it during exhalation. In the case of IPA exposure, a similar PBPK structure is used to describe the kinetics of the acetone produced from the metabolism of IPA. The resulting model is able to provide a coherent description of IPA and acetone kinetics in the rat and human for exposures to IPA by several routes: intravenous, intraperitoneal, oral, inhalation, and dermal. It is also able to consistently reproduce kinetic data for exposures of rats or humans to acetone. Thus, the model provides a validated framework for performing chemical-specific route-to-route extrapolation and cross-species dosimetry, which can be used in place of generic default calculations in support of risk assessments for IPA and acetone.

Development of a physiologically based pharmacokinetic model of trichloroethylene and its metabolites for use in risk assessment.

A physiologically based pharmacokinetic (PBPK) model was developed that provides a comprehensive description of the kinetics of trichloroethylene (TCE) and its metabolites, trichloroethanol (TCOH), trichloroacetic acid (TCA), and dichloroacetic acid (DCA), in the mouse, rat, and human for both oral and inhalation exposure. The model includes descriptions of the three principal target tissues for cancer identified in animal bioassays: liver, lung, and kidney. Cancer dose metrics provided in the model include the area under the concentration curve (AUC) for TCA and DCA in the plasma, the peak concentration and AUC for chloral in the tracheobronchial region of the lung, and the production of a thioacetylating intermediate from dichlorovinylcysteine in the kidney. Additional dose metrics provided for noncancer risk assessment include the peak concentrations and AUCs for TCE and TCOH in the blood, as well as the total metabolism of TCE divided by the body weight. Sensitivity and uncertainty analyses were performed on the model to evaluate its suitability for use in a pharmacokinetic risk assessment for TCE. Model predictions of TCE, TCA, DCA, and TCOH concentrations in rodents and humans are in good agreement with a variety of experimental data, suggesting that the model should provide a useful basis for evaluating cross-species differences in pharmacokinetics for these chemicals. In the case of the lung and kidney target tissues, however, only limited data are available for establishing cross-species pharmacokinetics. As a result, PBPK model calculations of target tissue dose for lung and kidney should be used with caution.

Evaluation of the uncertainty in an oral reference dose for methylmercury due to interindividual variability in pharmacokinetics.

An analysis of the uncertainty in guidelines for the ingestion of methylmercury (MeHg) due to human pharmacokinetic variability was conducted using a physiologically based pharmacokinetic (PBPK) model that describes MeHg kinetics in the pregnant human and fetus. Two alternative derivations of an ingestion guideline for MeHg were considered: the U.S. Environmental Protection Agency reference dose (RfD) of 0.1 microgram/kg/day derived from studies of an Iraqi grain poisoning episode, and the Agency for Toxic Substances and Disease Registry chronic oral minimal risk level (MRL) of 0.5 microgram/kg/day based on studies of a fish-eating population in the Seychelles Islands. Calculation of an ingestion guideline for MeHg from either of these epidemiological studies requires calculation of a dose conversion factor (DCF) relating a hair mercury concentration to a chronic MeHg ingestion rate. To evaluate the uncertainty in this DCF across the population of U.S. women of child-bearing age, Monte Carlo analyses were performed in which distributions for each of the parameters in the PBPK model were randomly sampled 1000 times. The 1st and 5th percentiles of the resulting distribution of DCFs were a factor of 1.8 and 1.5 below the median, respectively. This estimate of variability is consistent with, but somewhat less than, previous analyses performed with empirical, one-compartment pharmacokinetic models. The use of a consistent factor in both guidelines of 1.5 for pharmacokinetic variability in the DCF, and keeping all other aspects of the derivations unchanged, would result in an RfD of 0.2 microgram/kg/day and an MRL of 0.3 microgram/kg/day.

Investigation of the impact of pharmacokinetic variability and uncertainty on risks predicted with a pharmacokinetic model for chloroform.

A sensitivity and uncertainty analysis was performed on the Reitz et al. (Toxicol. Appl. Pharmacol., 1990: 105, 443) physiologically based pharmacokinetic (PBPK) risk assessment model for chloroform. The analytical approach attempted to separately consider the impacts of interindividual variability and parameter uncertainty on the predicted values of the dose metrics in the model, as well as on liver cancer risk estimates obtained with the model. An important feature of the analytical approach was that an attempt was made to incorporate information on correlation between important parameters, for example, the observed correlation between total blood flow and alveolar ventilation rate. Using the published PBPK model for chloroform, the best estimate of the average population risk based on the preferred pharmacodynamic dose metric (PTDEAD), representing cell death, is 9.2 x 10(-7); this estimate is more than 500-fold lower than the risk estimate of 5.3 x 10(-4) based on an alternative pharmacokinetic dose metric (AVEMMB), which represents tissue adduct formation. However, when interindividual variability was considered the range of individual risks (from the 5th to the 95th percentile of the population) predicted with PTDEAD was extremely broad (from 3.0 x 10(-13) to 3.2 x 10(-4)), while individual risks predicted with AVEMMB only varied over a factor of four (from 1.9 x 10(-4) to 7.4 x 10(-4)). As a result, the upper 95th percentile of the distribution of individual risk estimates based on the preferred cell death metric were within a factor of three of the 95th percentile for the pharmacokinetic alternative. The crucial factor with respect to the much greater variability of chloroform risk estimates based on cell death is that the dose metric, PTDEAD, is exquisitely sensitive to variation of the parameters in the model defining the response of cells to the cytotoxicity of chloroform. Unfortunately, these key parameters are also highly uncertain, as well as strongly correlated. As a result it proved impossible to accurately quantify the additional impact of parameter uncertainty on the dose metrics and risk estimates for chloroform. In general, however, the approach used in this study should be useful for differentiating the impact of interindividual variability and parameter uncertainty on PBPK-based risk assessments of other chemicals where the sensitivity, uncertainty, and correlation of the key parameters are more limited.

Developing drug use evaluation criteria for parenteral fluoroquinolones.

The basic tenet of pharmaceutical care asserts that the delivery of optimal, cost-effective pharmacotherapy can be best achieved by identifying, resolving, and preventing drug-related problems. Drug use evaluation (DUE) is one of the primary tools used to achieve these ends. Fluoroquinolone antimicrobials meet Joint Commission criteria for targeting for DUE: the drugs are used in populations at high risk for adverse drug reactions, quality assurance or infection control committees target them for DUE, the drugs are costly, they may be suspected or known to be used inappropriately, and they are prescribed frequently. Outside this supplement, no published DUE criteria for parenteral fluoroquinolones currently exist. Suggested criteria include use in patients who would otherwise be candidates for oral fluoroquinolone therapy (for which published criteria exist) but who cannot use the oral route of administration due to gastrointestinal conditions predisposing to malabsorption or unavailability of the oral route; for severe infections due to gram-negative pathogens; as a replacement for aminoglycosides when ototoxicity or nephrotoxicity is a substantial risk; targeting to resistant pathogens (i.e., not as empiric therapy); and targeting to therapeutic use only (not for prophylaxis). The DUE process is crucial for ensuring safe, effective, appropriate, and economical drug therapy. It is an effective mechanism for evaluating the use of new agents and as an educational tool for clinicians in the postmarketing period.

Toward a rational approach to the issue of prescribing authority for pharmacists.

The issue of expanded prescriptive authority for pharmacists has been gaining momentum for some time and has resulted in legislation in California and Washington and clarification of legislation in Oregon allowing expanded prescribing prerogatives for pharmacists. In April 1982, the American Pharmaceutical Association Policy Committee on Professional Affairs recommended that a policy statement be adopted endorsing the concept that pharmacists have the independent authority to select and dispense pharmaceutical and therapeutic alternates. The importance of the pharmacist as a health professional strategically placed and generally qualified to contribute significantly to the optimization of drug therapy outcomes cannot be denied. The advocacy of independent authority for all pharmacists to select pharmaceutical alternates, and particularly therapeutic alternates, appears to be premature, however. Orderly transition and constructive evolution of expanded prescriptive authority for pharmacists requires: (1) a comprehensive, introspective self-analysis of the current status of pharmacy practice; (2) establishment of a communication system between pharmacist and physician that will optimize drug therapy; (3) improved recognition by pharmacy of the complexity involved in drug selection and patient monitoring; and (4) development of a process for establishing credentials that would certify the competency of pharmacists to perform defined prescribing functions.

Total parenteral nutrition. A brief review.

The ideal solution for total parenteral nutrition (TPN) should contain nutrients equivalent to those of a well balanced, oral diet. With that goal in mind, available solutions usually provide adult patients with approximately 3,000 ml. solution daily, which supply about 12 gm. nitrogen and 2,400 kcal, with vitamins and minerals added as required. (Infants require relatively greater amounts of fluids and calories per kilogram.) The most critical concern in TPN is that of fluid and electrolyte balance, which varies with the patient. In this paper, the composition of four commercial TPN solutions is tabulated, as are recommendations for trace elements and vitamins which should be included.

Physicochemical stability of a preanesthetic mixture of hydroxyzine hydrochloride and atropine sulfate.

The stability of a combination of hydroxyzine hydrochloride and atropine sulfate stored in syringes was studied. Syringes containing the two drugs were stored at 25 C and 3 C for ten days and analyzed at specific time intervals. Absorption spectra, chromatographic characteristics and pH were determined. Results showed the admixture to be stable for ten days at room temperature or under refrigeration. The technique used would probably not detect any significant degradation of atropine sulfate unless the reaction occurred with the hydroxyzine hydrochloride.