Practice functions necessary for the delivery of pharmaceutical care.

Pharmaceutical care is a concept outlining the responsibilities of individual pharmacists to individual patients. Although widely accepted on a philosophical basis, there is a lack of comprehensive information about the functions and responsibilities pharmacists undertake when providing pharmaceutical care. Pharmacy educators and practitioners at the faculty of pharmacy, University of Toronto, developed and informally tested a process that details the practice functions required of pharmacists when providing pharmaceutical care as originally defined.

Moment method for the estimation of mass transfer coefficients for physiological pharmacokinetic models.

In vitro and in vivo techniques have been utilized to estimate mass transfer coefficients for physiological pharmacokinetic models. No single method has been adopted for estimating this parameter, in part, due to the different model structures with which this parameter may be associated. A specific method has been derived to calculate mass transfer coefficients for non-eliminating membrane-limited tissue compartments. The present method is based on observed concentration-time data, and requires the calculation of the areas under the zero and first moment curves for plasma, and the first moment curve for the tissue. A Monte Carlo simulation technique was used to determine the percentage biases of the method based on a published model for streptozoticin and adriamycin. For the latter model, the method was compared to a non-linear regression parameter estimation technique.

Physiological pharmacokinetic model of adriamycin delivered via magnetic albumin microspheres in the rat.

The influence of magnetic albumin microspheres on the disposition of adriamycin was evaluated. Adriamycin concentrations were monitored in multiple rat tissues for 48 hr after its intra-arterial administration (2 mg/kg) as a solution and associated with magnetic albumin microspheres. The magnetic dosage form was targeted to a predefined tail segment with a magnetic field strength of 8000 G applied for 30 min after dosing. A physiological pharmacokinetic model was used to describe the disposition of adriamycin following its administration from either dosage form. The model developed for the data resulting from administration of adriamycin as a solution served as a foundation for the model developed for adriamycin resulting from the administration of adriamycin associated with the magnetic dosage form. The model for adriamycin following administration of the magnetic microspheres required additional relationships to describe the transport of adriamycin associated with the microspheres. For both models, the predicted adriamycin concentrations were in adequate agreement with the observed values. The present investigation demonstrates the use of a physiological pharmacokinetic modeling method to represent drug kinetics following its administration via a targeted drug delivery system.

Evaluation of drug delivery following the administration of magnetic albumin microspheres containing adriamycin to the rat.

The disposition of adriamycin following its intra-arterial administration in rats as a solution (control) or via magnetic albumin microspheres (treatment group) has been investigated. The rat tail was demarcated into three segments: T1, the pre-target site; T2, the target site; and T3, the post-target site. In both groups, 2.0 mg/kg of adriamycin HCl was injected into the ventral caudal artery in T1 through a T-piece cannula. A magnetic field of 8000 G was directed towards T2. The concentration of adriamycin was measured in the heart, kidney, liver, lung, serum, small intestine, spleen, T1, T2, and T3 as a function of time using an ion-pairing HPLC assay. Areas under the mean adriamycin concentration-time curves were used to determine two indices of drug delivery: the relative tissue exposure and targeting efficiency. It was demonstrated that the magnetically responsive albumin microspheres altered the tissue distribution of adriamycin in rats. Administration of drug via magnetic microspheres was shown to increase the relative drug exposure to both T2 and liver.

The pharmacokinetics of doxifluridine and 5-fluorouracil after single intravenous infusions of doxifluridine to patients with colorectal cancer.

The disposition kinetics of a new 5-fluorouracil prodrug, 5'-deoxy-5-fluorouridine (5'dFUR, doxifluridine), were investigated in six patients with colorectal carcinoma. Each patient randomly received two single intravenous doses of 5'dFUR (2 and 4 g.m-2) on separate days. Plasma concentrations of 5'dFUR fell rapidly with terminal half-lives ranging from 16.1 to 27.7 min. A disproportionate increase in the area under the curve with increasing dose was seen in most patients. Doubling the dose resulted in a 40% decrease in nonrenal clearance (0.60 to 0.37 l.min-1) but no apparent change in renal clearance (0.32 to 0.29 l.min-1) or steady-state apparent volume of distribution (19.8 to 20.4 l). The mechanism for dose-dependence of 5'dFUR appears to be primarily due to nonlinear elimination associated with nonrenal processes rather than nonlinear plasma protein or tissue binding.

Area method for the estimation of partition coefficients for physiological pharmacokinetic models.

A new technique, the area method, is derived for the determination of partition coefficients for both blood-flow limited and membrane limited physiological pharmacokinetic models. This method was compared to a standard technique by Monte Carlo simulation. Partition coefficients were calculated for the blood-flow limited case for both eliminating and noneliminating organs. It was found that the area method compared favorably to a standard technique and was less prone to error. This may be attributed to the more subjective interpretation as to which data points are included in the terminal phase, since the standard method relies on the accurate determination of the terminal slope for the calculation of partition coefficients. Both methods are satisfactory for the calculation of partition coefficients with the area method being more accurate and precise.

Analysis of p-aminobenzoic acid and its metabolites in urine and plasma by ion pair HPLC in the NBT-PABA pancreatic function test.

An ion pair HPLC method which can simultaneously detect the major metabolites of an exocrine pancreatic function testing agent (NBT-PABA) in plasma and urine has been developed. This assay has been applied to a pharmacokinetic study of PABA and its metabolites in 3 healthy adult volunteers following the oral administration of 1 g NBT-PABA. The 6 h testing period currently used to collect urine following the NBT-PABA ingestion is adequate for the recovery of PABA and its metabolites. Plasma determination of these compounds may provide an improved evaluation of the pancreatic performance in patients with abnormal liver or kidney function.

Quantitation of the release of doxorubicin from colloidal dosage forms using dynamic dialysis.

The release of doxorubicin from submicrometer bovine serum albumin (BSA) microspheres has been quantitated using dynamic dialysis. Mathematical models have been proposed based on zero- or first-order release of drug from solid colloidal matrices. The models also account for the permeability constant of the dialysis membrane. Results obtained by the dynamic dialysis technique resemble those obtained using a conventional dissolution method. The release of doxorubicin from the microspheres can be adequately described by a biphasic zero-order model.

Influence of smoking and gender on the disposition kinetics of metoprolol.

The purpose of this study was to examine the influence of cigarette smoking and gender on the pharmacokinetics of metoprolol. Eighteen volunteers with no evidence of clinical disease each randomly received the following doses of metoprolol tartrate: 100 mg orally, 200 mg orally and 20 mg as a constant-rate intravenous infusion over 20 min. The only significant difference between smokers (S) and nonsmokers (NS) was that S had a larger steady-state volume of distribution (3.3 vs 2.5 l/kg). There were no differences in half-life, systemic clearance or bioavailability (f). No differences were observed between males (M) and females (FM) for any of the kinetic parameters examined. Systemic bioavailability varied markedly between subjects (range: 15 to 92%). In fifteen of the eighteen subjects, f was higher after the 200-mg dose compared to the 100-mg dose. These results suggest that metoprolol may be subject to saturable presystemic elimination and extend the previous observations of Johnsson et al. [1] who showed that f increased from 31% to 46% when doses were increased from 20 to 100 mg. However, the difference in f as the dose is increased is unlikely to be clinically significant since the mean difference is smaller than the variation in f among subjects.

Nonlinear pharmacokinetic characteristics of 5-fluorouracil (5-FU) in colorectal cancer patients.

The nonlinear disposition kinetics of 5-fluorouracil (5-FU) were investigated in 6 patients with colorectal carcinoma. Each patient randomly received two single, intravenous doses of 5-FU (7.5 and 15 mg/kg) on separate days. Venous blood and urine samples were collected just prior to and for 5 h after drug administration. In addition to the kinetic studies, the in vitro whole blood/plasma concentration ratio and stability of 5-FU at 37 degrees C were determined in whole blood from normal volunteers and from 5 patients with colorectal carcinoma. A disproportionate increase in area under the curve and corresponding decrease in total body clearance with increasing dose was observed suggesting dose-dependent behavior of 5-FU. Doubling the dose was accompanied by a 36% decrease in nonrenal clearance but no apparent change in renal clearance. Therefore, the mechanism for dose-dependent elimination appears to be primarily associated with nonrenal processes. The mean 5-FU half-life following the high dose was nearly twice as long as that observed for the low dose (12.3 versus 6.2 min). The log-linear decline in plasma concentrations and increase in half-life with dose suggest the potential role of product-inhibition as an explanation for the observed nonlinearity in 5-FU elimination. The present study demonstrates that 5-FU degrades when incubated in whole blood. This most likely reflects metabolism in red blood cells or other blood-formed elements since 5-FU was stable in plasma. Although degradation in whole blood occurs, the estimated whole blood clearance does not contribute significantly to the observed total body clearance value. The findings suggest the possibility of pulmonary clearance of 5-FU.

Determination of pharmacokinetics of cocaine in sheep by liquid chromatography.

Cocaine was administered as 1-, 2-, and 4-mg/kg intravenous bolus doses to each of six sheep. Plasma samples were collected as a function of time and assayed for cocaine using reversed-phase ion-pair HPLC. The assay involved double extraction with ether and UV detection at 229 nm. Using 2 mL of plasma, levels of 1 ng/mL of cocaine can be measured. The concentration versus time data obtained for the plasma samples were analyzed by a "noncompartmental" method. The pharmacokinetic parameters of cocaine in sheep had mean values of 4.0 L/kg, 3.5 L/kg, and 0.29 L X min-1 X kg-1 for Vd, Vdss, and CL respectively. The clearance of cocaine in sheep was much higher than cardiac output. Pulmonary first-pass effect has been suggested as the possible explanation for the large clearance of cocaine in sheep.

Reversed-phase ion-pair high-performance liquid chromatography of adriamycin and adriamycinol in rat serum and tissues.

An ion-pair reversed-phase high-performance liquid chromatographic method is presented for the determination of adriamycin and adriamycinol concentrations in rat serum and tissues. The scheme for developing the chromatographic conditions is discussed. A good separation of adriamycinol and adriamycin was obtained by using a high sodium lauryl sulphate concentration in the mobile phase. The retention times of adriamycinol, adriamycin and daunomycin (internal standard) were less than 3 min with no interfering peaks from endogenous constituents. A protein precipitation method was used to prepare the serum and tissue samples for injection.

Analysis of 5'-deoxy-5-fluorouridine and 5-fluorouracil in human plasma and urine by high-performance liquid chromatography.

A relatively simple and sensitive high-performance liquid chromatographic (HPLC) method is described for measuring the two anticancer drugs 5'-deoxy-5-fluorouridine (5'dFUR) and 5-fluorouracil (5-FU) in human plasma and urine. The procedure for plasma includes solvent extraction using ethyl acetate-isopropyl alcohol (85:15) followed by silica gel column chromatography to separate these compounds from constituents normally occurring in plasma. The analysis by reversed-phase HPLC is performed on a phenyl column using an aqueous mobile phase with ultraviolet detection (280 nm). The overall recovery from plasma was 61% and 65% for 5'dFUR and 5-FU, respectively. The sensitivity limit of the assay for both compounds was 50 ng/ml of plasma. Analysis of these compounds in urine did not require the silica column chromatography isolation step.

Methotrexate: bioavailability and pharmacokinetics.

Six adult patients with squamous cell carcinoma of the head and neck were treated with single low doses of methotrexate (MTX) (30 mg/m2) iv, im, and orally in the form of commercial tablets. A randomized crossover design was employed. Plasma concentrations were measured by a modified EMIT assay over a period of 24 hours following each dose. The mean (+/- SD) parameters following iv MTX were as follows: total-body clearance, 124 (36) ml/minute; Vss, 0.56 (0.18) L/kg; V lambda, 0.69 (0.24) L/kg; and beta-half-life, 3.20 hours. The absolute systemic bioavailability of the oral tablets was 36% (+/- 10%). After im administration, the systemic bioavailability was 93% (+/- 14%). Dose-dependent gastrointestinal absorption is suggested as the mechanism for the low availability of the oral tablets. Administration of MTX by the oral route will require further study to determine the optimal method of dosing.

Theophylline serum concentrations in ambulatory patients with chronic obstructive pulmonary disease.

A two-part study was designed to investigate the application of theophylline serum concentration data at a Veterans Administration Medical Center. The investigation was unique in its use of ambulatory patients instead of hospitalized patients as study subjects for assessing the use of laboratory tests. As has been found in other studies that examined different drugs and involved hospitalized subjects, this investigation discovered significant problems in the ordering, application, and documentation of these data when judged against established criteria. There was no significant difference in the appropriate use of these drugs between physicians specializing in pulmonary versus general medicine. Of clinical importance also are the findings that confirm a positive correlation between the proper use of these tests and improvement in patient outcome, and the demonstrated relationships between clinical symptoms and subtherapeutic and toxic serum concentrations of theophylline.