Janis J. MacKichan

Pharmacokinetic Consequences of Drug Displacement from Blood and Tissue Proteins

SummaryDisplacement of one drug by another from blood and/or tissue protein will alter the pharmacokinetic behaviour of the displaced drug. For restrictively cleared drugs, displacement from blood proteins will cause only a transient change in free drug concentration and hence in pharmacodynamic response, so that dosage adjustments are rarely necessary. Total drug concentrations, however, are decreased and must be appropriately interpreted. Binding displacement from blood and/or tissue will also shorten the half-lives of these drugs, thus magnifying peak-trough differences during a dosage interval. These theoretical expectations are supported by examples of drug displacement interactions involving warfarin and phenytoin.Although total drug concentrations in blood will be unchanged, free drug concentrations will be increased and drug response enhanced for non-restrictively cleared drugs as a result of displacement from blood protein, possibly necessitating a dosage reduction.

Influence of volume shifts on drug binding during equilibrium dialysis: Correction and attenuation

A time-dependent volume shift from buffer to plasma, which occurs during equilibrium dialysis, decreased the protein binding of disopyramide and its capacity constant, and had no effect on the binding association constant. The volume-dependent decrease in disopyramidine binding may be corrected for by use of a derived equation. Inclusion of dextran, 2.5% (w/v), and use of a thick, low molecular weight cutoff membrane was the most effective technique in attenuating the volume shift. The plasma (serum) protein binding of the basic drugs lidocaine, disopyramide,propranolol, and diazepam was decreased when protein was diluted to 88 % or less of its undiluted concentration as a consequence of the volume shift. The protein binding of clofibrate, a highly bound acid drug, was more sensitive to volume shifts than the four basic drugs. Correction of drug binding for volume shifts was reasonably successful for most drugs. The highest binding measured for all drugs was associated with the lowest volume shift.

Specific HPLC method for the separation of verapamil and four major metabolites after oral dosing

Abstract We have developed a high performance liquid chromatographic (HPLC) method which resolves verapamil, norverapamil, D620, D617 and what we believe to be another verapamil metabolite which has been previously unreported. An alkyl-phenyl column is used with a mobile phase of 0.005% sulfuric acid in methanol. The extraction recoveries of verapamil, norverapamil and the internal standard (imipramine) from plasma ranged between 98% and 104%. The day-to-day, and within-day coefficients of variations for verapamil and norverapamil at plasma concentrations of 7.3 and 233 ng/ml ranged between 1.7 and 6.1%. The limit of sensitivity was slightly less than 1 ng for both verapamil and norverapamil. Chromatograms of extracts of serum and urine obtained from five normal subjects who took single oral verapamil doses, indicated the presence of verapamil, norverapamil, and two other known metabolites. Chromatograms of serum extracts also indicated an additional peak which is probably another verapamil metabolite.

Specific high performance liquid chromatographic determination of quinidine in serum, blood, and urine.

A reversed-phase high performance liquid chromatographic method for determination of quinidine in serum, blood, and urine has been developed. An alkylnitrile column is used with a mobile phase of acetonitrile in an acetate buffer. The method was rigorously tested and shown to be specific for quinidine using the following methods: (a) comparison of capacity factors among methanolic reference standards of quinidine, known metabolites, and 36 other drugs; (b) comparison of the quinidine capacity factor with the capacity factors from components in patient sera and urines, from which quinidine was selectively removed by thin-layer chromatography; and, (c) correlation of quinidine concentrations in patient sera using ultraviolet absorbance versus fluorescence detection. Application of the method to a single-dose pharmacokinetic study, including serum protein binding and blood/serum concentration ratio measurements, demonstrates excellent sensitivity of the method.

High-Performance Liquid Chromatographic Method for the Determination of Metoclopramide in Plasma

Abstract A reversed-phase high performance liquid chromatographic method for the determination of metoclopramide in plasma has been developed. Metoclopramide was extracted from alkalinized plasma (0.25 − 0.5 ml) into methyl-t-butyl ether, injected onto an alkylnitrile column and eluted with a mobile phase of methanol and tetrahydrofuran in acetate buffer, pH 4.3. The eluate was monitored with a variable wavelength UV detector at 309 nm. Extraction efficiencies for metoclopramide and the internal standard (a dipropyl analog of procainamide) ranged from 89 to 93%. The limit of sensitivity for the method was 2.5 ng/ml when 0.5 ml of plasma was extracted. Application of the method to single dose pharmacokinetic studies was demonstrated by the analysis of plasma samples following the administration of a single 10 mg oral dose of metoclopramide hydrochloride to two healthy volunteers.

Oral Enoximone Pharmacokinetics in Patients with Congestive Heart Failure

The pharmacokinetics of enoximone and its sulfoxide metabolite were determined following administration of a single oral dose of 1 or 2 mg/kg in seven patients with congestive heart failure, and in two normal volunteers following a single 75‐mg capsule, and were compared to those published previously. Plasma concentrations of the metabolite were higher than enoximone, and their terminal slopes were parallel. Enoximone and enoximone sulfoxide plasma concentration‐time data were fitted to a simple model that included a lag time. Absorption half‐lives in patients and normal volunteers averaged 17 minutes; the elimination half‐life of enoximone in patients averaged 2.9 hours, and was slightly prolonged as compared with normal volunteers. The elimination half‐life of enoximone sulfoxide averaged 17 minutes in patients and normal volunteers, and was considerably shorter than that reported in other studies. The oral clearance of enoximone in patients averaged 99 L/hr, and was lower than that observed in normal volunteers. The ratio of the area under the plasma concentration time curve of enoximone sulfoxide to enoximone averaged 4.7 in patients, and was similar to that observed in normal subjects. Enoximone oral clearance and the ratio of metabolite to parent were related to liver blood flow (determined by indocyanine green). Enoximone is 65% bound to albumin, which accounts for most of the drug bound to human plasma protein.

The Pharmacokinetics of Alfentanil in Gynecologic Surgical Patients

The pharmacokinetics and serum protein binding of alfentanil during continuous intravenous infusion were determined in 11 women who were either healthy (American Society of Anesthesiologists [ASA] physical status 1) or had mild systemic disease (ASA physical status 2). Anesthesia was induced with intravenous thiopental 2 mg/kg and alfentanil 50 μg/kg and maintained with constant intravenous alfentanil infusions of 1–3 μg/kg/min until approximately ten minutes before the end of surgery. Venous blood samples were obtained after the bolus of alfentanil was administered and at various times during and after the alfentanil infusion. Serum alfentanil concentrations were measured by gas‐liquid chromatography. There was considerable interpatient variability in alfentanil pharmacokinetics and serum protein binding. The mean ± SD alfentanil serum clearance, volume of distribution at steady state (Vss), and elimination half‐life were 5.2 ± 2.0 mL/min/kg, 0.47 ± 0.1 L/kg, and 97 ± 52 minutes, respectively. The mean fraction of alfentanil unbound in serum (fu) was 0.18 ± 0.08. There was a time‐dependent decrease in alfentanil serum clearance that correlated with increasing duration of surgery. This decrease in clearance resulted in a prolonged alfentanil half‐life. These results indicate there is considerable interpatient variability in the pharmacokinetic parameters and serum protein binding of alfentanil in these patients and suggest that the infusion rate of alfentanil during maintenance anesthesia should be adjusted for individual patient response. Infusion rates may need to be tapered during prolonged operations.

Determination of pindolol in human plasma and urine by high-performance liquid chromatography with ultraviolet detection.

This paper presents a rapid, simple and economical method for assaying pindolol concentrations in plasma and urine by high-performance liquid chromatography using ultraviolet detection. It is sensitive enough for use in single-dose pharmacokinetic studies and may also be used to determine pindolol concentrations in the plasma from patients taking the drug, provided that the patient is not taking any of the drugs which interfere with the method. Drugs which were found to interfere with the pindolol peak are quinidine, n-acetylprocainamide and lidocaine. Disopyramide, oxprenolol and levobunolol interfered with the internal standard peak.

Clinical pharmacology of nicorandil in patients with congestive heart failure

Nicorandil is a nicotinamide derivative with a potential role in human therapeutics because of its potent vasodilating properties. The pharmacokinetics of oral nicorandil administration and the relationships between plasma nicorandil concentration and hemodynamic responses were examined in 25 patients with moderate to severe congestive heart failure. The dose range from 10 to 60 mg was studied. Elimination half‐life for this dose range was substantially longer than that previously reported in normal volunteers. Total area under the curve increased in a curvilinear fashion with progressive dose increments, indicating a disproportionate increase in systemically available drug at higher doses. Hemodynamic responses generally correlated well with plasma nicorandil concentration, with rapid loss of cardiovascular activity corresponding to the efficient clearance of nicorandil.

Evaluation of fluorescence immunoassay for total and unbound serum concentrations of disopyramide.

Summary The accuracy of determining disopyramide concentrations in 80 serum samples by high-performance liquid chromatography (HPLC) and fluorescence immunoassay (FIA) on 2 consecutive days was similar. The precision of both methods was excellent. The interday precision of FIA was superior to HPLC at nominal concentrations of 1.5 and 3.0 mg/L, but was similar at 7.0 mg/L. Following equilibrium dialysis of 40 serum samples, the unbound concentration of disopyramide determined by a modified FIA method underestimated by 16% the unbound concentration determined by a reference method. The discrepancy may be avoided by preparing standards in the appropriate buffer. Fluorescence of disopyramide optical isomers at similar concentrations were identical. It is concluded that FIA for determining plasma concentrations of disopyramide is accurate and precise, and may be modified to accurately determine unbound concentrations following separation of plasma water and protein.