Robert Forney

The Effect of Erythromycin on the Disposition Kinetics of Warfarin

Erythromycin is generally regarded as innocuous in regard to adverse interactions with other drugs. Recently, however, its potentiation of theophylline and warfarin has been reported. The present investigation defined more specifically the kinetics of the interaction between erythromycin and warfarin. Warfarin kinetics were evaluated in 12 normal subjects who took a single 1 mg/kg dose of warfarin with and without erythromycin. Erythromycin (250 mg p.o.) every 6 h for 8 days decreased warfarin clearance by 14% (p less than 0.001). Warfarins apparent volume of distribution was not affected. Further, the effect of erythromycin was greatest among subjects whose control phase warfarin clearance was relatively slow, and least among those whose control phase warfarin clearance was relatively fast. The magnitude of the decrease in warfarin clearance correlated negatively with control warfarin clearance (r = -0.89, p less than 0.005). These data are consistent with the interpretation that erythromycin can potentiate warfarin-induced hypoprothrombinemia by slowing warfarin clearance.

Jamaican vomiting sickness in Toledo, Ohio

The endemic illness of Jamaica known as ackee poisoning is reported for the first time in the United States. The toxic exposure resulted from the consumption of canned ackee. The epidemiology, diagnosis, theoretical mechanism, and possible therapy of this disease are discussed.

Theophylline kinetics: dose dependency and single sample prediction of clearance

Theophylline clearance was measured at 3 doses (2, 4 and 6 mg/kg) in 10 young, healthy adult subjects. Clearance decreased as the dose of theophylline increased going from 0.064 +/- 0.016 to 0.052 +/- 0.011 1.h-1.kg-1 at the 2 and 6 mg/kg doses, respectively (p less than 0.02). A simplified method for estimating theophylline clearance was tested using single plasma concentrations of theophylline and assuming a constant value (0.5 l/kg) for volume distribution of theophylline. This method gave the best results when samples were drawn at 12 or 24 h after a 2 or 4 mg/kg intravenous dose of theophylline, respectively, and was effectively applied in estimating the quantitative impact of cimetidine administration on theophylline clearance.

Monitoring phenytoin in salivary and plasma ultrafiltrates of pediatric patients

The plasma binding of phenytoin and the relationship between phenytoin concentrations in salivary and plasma ultrafiltrates were evaluated in pediatric epileptic patients aged 2-15 years. Paired samples of plasma and saliva were ultrafiltered through an Amicon YMT membrane. Phenytoin concentrations were measured by a gas-liquid chromatography procedure. The phenytoin free fraction among pediatric epilepsy patients not taking valproic acid was normally distributed with a mean (+/- SD) of 9.2 +/- 1.8%. The mean (+/- SD) free phenytoin fraction among patients also taking valproic acid was 13.2 +/- 4.5%. Salivary ultrafiltrates exhibited a close correspondence with plasma ultrafiltrate concentrations, and the ratio of salivary to plasma ultrafiltrate concentrations was 1.06 +/- 0.15. Substantial intraindividual variation in the phenytoin free fraction and the increase in free fraction among patients on valproic acid emphasize the importance of using plasma unbound levels for monitoring phenytoin. The close agreement between plasma and salivary ultrafiltrate concentrations suggests that the latter will provide a practical noninvasive means of monitoring phenytoin.

Analysis of Succinylcholine in Tissues and Body Fluids by Ion-Pair Extraction and Gas Chromatography-Mass Spectrometry

The neuromuscular blocking agent succinylcholine (SCh) has been identified and quantitated in biological material using gas chromatography-mass spectrometry. The bisquaternary ammonium compound SCh is extracted from tissue homogenates or body fluids into dichloromethane as an ion pair with hexanitrodiphenylamine (DPA). The evaporated ion pair residue is demethylated with sodium benzenethiolate to form the corresponding tertiary amine which is identified and quantitated by gas chromatography-mass spectrometry using a glass capillary column coated with SE 52. In the quantitative analysis deuterated SCh is used as internal standard. The instrument is focussed on m/z 58 for demethylated SCh and m/z 62 or 64 for the internal standard. Concentrations as low as 5 ng SCh iodide/g tissue or body fluid are easily detected.

The use of single sample clearance estimates to probe hepatic drug metabolism: handprinting the influence of cigarette smoking on human hepatic drug metabolism

1. Conditions were examined under which estimates of drug clearance made from a single measurement of plasma concentration effectively represented multiple-sample estimates of clearance for quinidine, valproic acid, unbound valproic acid, and lorazepam. When plasma concentrations were measured at various post-dose times, both individual and mean values of single-sample clearance estimates, CL, corresponded closely to multiple-sample clearance estimates. Best post-dose sampling times were: quinidine, 8 h; valproic acid, 24 h; and lorazepam, 24 h. 2. Single-sample clearance estimates, CL, were calculated for seven drugs employed as probes of human hepatic drug-metabolizing enzymes. Valproic acid was used to probe microsomal and peroxisomal beta-oxidase activity; antipyrine, phenytoin, quinidine, carbamazepine, and theophylline were used as probes of hepatic mixed-function oxidases (MFO), and lorazepam as a probe for UDP-glucuronosyltransferase activity. 3. A clearance index (CI, namely probe CL for smokers divided by probe CL for non-smokers) was calculated for each probe. The effect of cigarette smoking (and presumably polycyclic aromatic hydrocarbon exposure) on all probe CL values was consolidated and plotted as the logarithm of the CI to produce a handprint of drug metabolizing enzyme activity for cigarette smokers. 4. Only theophylline CL was significantly faster among smokers than non-smokers (P less than 0.01). 5. We conclude that the use of multiple probes of MFO activity when given in a single-dose, single-sample protocol for structuring handprints represents a minimally invasive and useful approach to characterize xenobiotic-mediated effects on hepatic MFO.

Correlation of Plasma Concentration and Effects of Succinylcholine in Dogs

The study was undertaken to determine the pharmacokinetic values for half-life, volume of distribution, and clearance for succinylcholine (SCh) based on measurements of the drug in plasma. Three intravenous (i.v.) doses (0.5, 1.0, and 5.0 mg/kg) were compared to study the time course of paralysis and recovery and to describe the relationship of plasma concentration (Cp) and the pharmacologic effects of SCh in canines. The physiologic response to the neuromuscular blocking drug was monitored using train-of-four stimulation of the left sciatic nerve and recording the response of the corresponding gastrocnemius muscle. Time courses for paralysis and recovery were monitored, and the results were used to predict the kinetic values for the pharmacologic effects. Blood samples were taken following drug administration for direct pharmacokinetic estimations. SCh determinations were performed using ion-pair extraction, chemical demethylation, and gas chromatography with nitrogen phosphorous detection. Both kinetic analyses showed the beta half-life for SCh to be approximately 5 min for all doses. SCh has a distribution half-life of less than 1 min. There appears to be a threshold Cp below which neuromuscular function returns. Recovery following SCh induced paralysis had a rapid onset, but the duration of paralysis and the rate of recovery were especially prolonged for the 5.0-mg/kg treatment group.

Impact of cefaclor on the pharmacokinetics of theophylline.

The influence of cefaclor taken for 8 days (250 mg every 8 h) on the pharmacokinetics of a single intravenous dose of theophylline (2 mg/kg administered on the 8th cefaclor day) was studied in a crossover fashion among 11 healthy adults (10 men and one woman). Theophylline concentrations were measured serially for 12 h by an immunofluorescence polarization technique. No influence of cefaclor was detectable on theophylline clearance, half-life, or volume of distribution. It is concluded that cefaclor and theophylline can be administered together safely.

The influence of storage temperature and chemical preservation on the stability of succinylcholine in canine tissue.

Succinylcholine (SCh) has been detected six months postmortem in liver, kidney, and injection site muscle of rats given 10 to 200 mg/kg by intramuscular injection. SCh stability was studied in canine tissue to evaluate three storage temperatures and two chemical preservatives at three time periods after injection. Nine mongrel dogs weighing 17.2 to 28 kg were divided equally into three groups and administered either 0.5, 1.0, or 5.0 mg SCh/kg intravenously into the cephalic vein. Liver, kidney, and gastrocnemius muscle were removed 90 min post-injection and divided into twelve portions. Each portion was treated with embalming fluid, physostigmine, the combination (50/50), or nothing. Chemically treated tissues and nontreated tissues were then stored at either 27, 5, or -20 degrees C for a period of up to forty days. Tissue portions were analyzed using ion-pair extraction, chemical demethylation, and gas chromatography with nitrogen phosphorous detection. Stability of SCh was greatest for samples stored at -20 degrees C and preserved with the combination of embalming fluid plus physostigmine. Kidney concentrations of SCh were significantly higher than those in liver or muscle at all doses. SCh was detected 24 h post-injection in all cases. By 40 days, only trace amounts of SCh, if any, could be detected in samples stored at room temperature with no chemical preservatives.

Use of plasma unbound drug concentrations in adjusting phenytoin doses

Summary The application of a Bayesian feedback algorithm for phenytoin (PHT) dosing adjustments was modified empirically to take advantage of measurements of plasma unbound PHT concentrations in the estimation of Km values. Doses were calculated to achieve steady-state unbound PHT nadirs of 1.2 mg/L with an allowable range of 0.9–1.5 mg/L. The success of this approach was compared with that of a routine strategy encompassing the use of monitored total plasma PHT concentrations and no estimates of kinetic parameters. Allowing up to a double feedback of monitored values, the Bayesian approach was better than the routine procedure in predicting doses that led to PHT concentration within the targeted range (p < 0.005). The approach to optimizing PHT dosing described herein offers the advantage of rapidly converging on near-optimal therapy for those patients who are already on PHT but whose seizures are not suitably controlled, and may be useful even for patients who exhibit abnormal PHT plasma protein binding, such as those who also must take valproic acid.