Anthony J. Piraino

Effect of renal impairment on the pharmacokinetics and pharmacodynamics of desirudin

To investigate the pharmacokinetics and pharmacodynamics of desirudin in subjects with various degrees of renal impairment in comparison with subjects with normal renal function.

Diazepam concentrations in parotid saliva, mixed saliva, and plasma

The concentration of diazepam in the plasma and saliva of 9 normal human subjects receiving a single oral dose of diazepam (10 mg) over an 8‐hr period was determined by gas‐liquid chromatography/electron capture analysis. In addition, the binding of diazepam to plasma protein in these subjects was determined using equilibrium dialysis at specific time intervals corresponding to periods of plasma and saliva collection. A linear relationship was found between diazepam concentration in plasma and that in both mixed and parotid saliva, over plasma concentrations ranging from 196 ± 16.4 to 74.8 ± 10.3 ng/ml. The elimination constants (−Ke) were 0.13, 0.17, 0.18 for diazepam disappearance from plasma, parotid saliva, and mixed saliva, respectively. The mean parotid concentration ratio was 0.035 and the mixed saliva/plasma diazepam concentration ratio was 0.029. These were not affected by variations in plasma diazepam levels. The percentage of the plasma diazepam concentration in both parotid saliva (3.5%) and mixed saliva (2.9%) was of the same order as the fraction of diazepam found to be free from plasma protein in these subjects (2.0% to 3.5%). The results indicate that there is no significant difference between parotid saliva and mixed saliva concentrations over a period of 8 hr after a single oral dose of diazepam. The results strongly suggest that the appearance of diazepam in saliva may provide an alternate, non invasive method of determining plasma diazepam levels.

Pharmacokinetics of Multiple Daily Transdermal Doses of Nicotine in Healthy Smokers

The plasma concentration–time profiles and pharmacokinetics were characterized for nicotine and its major metabolite, cotinine, after multiple daily application of a nicotine user-activated transdermal therapeutic system (UATTS) to nine healthy smokers. The volunteers abstained from smoking 24 hr prior to and during the course of the study. A 10-cm2 system (designed to deliver 75 µg/cm2/hr) was applied every 24 hr for 5 days, with serial blood samples taken on Days 1 and 5 and after system removal on Day 5. Generally, the nicotine UATTS was well tolerated. Predose nicotine concentrations on Days 3 to 5 indicated that steady state was reached by Day 3. The nicotine pharmacokinetic parameters for Day 1 and Day 5 were similar: the mean (SD) AUC(0-24) values for Days 1 and 5 were 271.7 (50.7) and 311.7 (55.0) ng · hr/ml, the mean (SD) Cmax values were 16.3 (2.6) and 16.8 (2.9) ng/ml, and the median (range) Tmax values on Days 1 and 5 were 12 (9–24) hr and 12 (0–24) hr, respectively. There was only slight or no accumulation of nicotine after multiple dosing as indicated by the Day 5 to Day 1 AUC and Cmax ratios of 1.15 (0.09) and 0.98 (0.06), respectively. Overall, the UATTS system maintained relatively constant plasma nicotine concentrations and is suitable for once-daily application.

Comparative Pharmacokinetics and Bioavailability of Nitroglycerin and its Metabolites from Transderm‐Nitro, Nitrodisc, and Nitro‐Dur II Systems Using a Stable‐Isotope Technique

The pharmacokinetics and bioavailability of nitroglycerin (GTN) and its metabolites, 1,2‐glyceryl dinitrate (1,2‐GDN) and 1,3‐glyceryl dinitrate (1,3‐GDN), were compared after a single 14‐hour application of Transderm‐Nitro (Ciba‐Geigy, Summit, NJ), Nitrodisc (GD Searle, Chicago, IL), and Nitro‐Dur II (Key Pharmaceuticals, Kenilworth, NJ) systems to 18 healthy male subjects on 3 separate occasions. A 14‐hour intravenous infusion of 15N‐labeled GTN was given simultaneously to correct for changes in systemic clearance during the application of each system. Plasma concentrations of 15N‐labeled GTN, unlabeled GTN, and their corresponding dinitrate metabolites were measured using a gas chromatography/mass spectrometry method. Results showed that the plasma concentration profiles of nitroglycerin and its metabolites for the three systems were similar during and after system removal. Mean (SD) total amounts (AUCp × CLiv) of GTN transdermally available after adjustment for 15N‐labeled GTN clearance were 5.3 (2.1), 5.3 (2.0), and 5.4 (2.6) mg for Transderm‐Nitro, Nitrodisc, and Nitro‐Dur II, respectively. Mean (SD) AUC values for 1,2‐GDN were 44.6 (15.8), 44.3 (16.1), and 42.8 (19.3) ng • h/mL for the 3 systems. Corresponding AUC values for 1,3‐GDN were 9.3 (2.9), 9.7 (2.9), and 8.7 (3.0) ng • h/mL. Statistical analysis of the log‐transformed data based on 90% conventional confidence interval showed that all 3 systems delivered equivalent amounts of nitroglycerin into the systemic circulation. The AUC ratios for 1,3‐GDN to GTN, but not 1,2‐GDN to GTN, were statistically different for the intravenous and transdermal routes during all 3 system applications, indicating that the formation and metabolism of 1,3‐GDN was dependent on route of administration.

Correlations of parotid saliva and blood ethanol concentrations

Abstract This paper is devoted to the detection and quantitation of blood and parotid saliva ethanol in both human subjects and rats. The human ethanol saliva-plasma ratio has been determined to be 1.04 utilizing a collection technique which is non-invasive and easily performed. The rat ethanol saliva-plasma ratio has been found to be 1.21 with a direct cannulation technique of the parotid duct. Differences between the human and rat ratios have been attributed to the method of salivary gland stimulation. The human parotid gland was stimulated by a reflex action of an organe-flavored lozenge, whereas the rat parotid gland was stimulated by a direct infusion of pilocarpine. The results indicate that the rat parotid secretion of ethanol is very similar to the human secretions, and the rat could possibly be utilized as an animal model for future alcohol salivary studies.

Pharmacokinetic Disposition of Multiple-Dose Transdermal Nicotine in Healthy Adult Smokers

The pharmacokinetics and cardiovascular effects of nicotine and its major metabolite, cotinine, were characterized during repeated once-daily application for 5 days of a 30-cm2 nicotine transdermal system, Nicotine TTS (Habitrol), to nine healthy, black, adult, male smokers. Subjects abstained from smoking throughout the study. Pharmacokinetic analysis indicated that nicotine was delivered from Nicotine TTS for the 24-hr application period averaging 0.76 mg/ cm2/24 hr, and at a relatively constant rate compared to other modes of drug administration. The transdermal clearance of nicotine, 1351 ml/min, coincided with reported values following intravenous nicotine administration; however, the terminal-phase half-life, 5.0 hr, did not. An analysis of the components of variance contributing to the variability in nicotine delivery from repetitive application of Nicotine TTS indicated that the in vivo transdermal permeation of nicotine is rate limited by both the device and the intrinsic skin conductivity. Clinical cardiovascular side effects were negligible as an apparent result of subclinical vasopressive nicotine concentrations, although drug activity with regard to other effects was manifested.

Managing Medication in the Elderly

The elderly receive 30% of all prescriptions and buy 40% of all OTC drugs. In addition to the potential pitfalls inherent to age-related changes in bioavailability and clearance, there are less well-known hazards in prescribing for the aged. Many drugs, for example, have powerful anticholinergic properties, and a generic agent may differ markedly from both the brand drug and another generic version.

Excretion of Barbiturates into Induced Parotid Saliva of the Rat

Anesthetic doses of barbiturates administered to rats were excreted into the parotid saliva. Plasma-saliva concentration ratios were compared to several physicochemical parameters-lipid-water partition coefficient (L/W), degree of ionization, and plasma protein binding-of which L/W appears to correlate best with the excretion of barbiturates into parotid saliva.

Pharmacokinetics of a single transdermal dose of nicotine in healthy smokers

Abstract The plasma concentration-time profiles for nicotine and its major metabolite, cotinine, were characterized after a single application of a nicotine user-activated transdermal therapeutic system (UATTS) to the upper forearm of eight healthy smokers. The volunteers abstained from smoking for 12 h prior to, and during the course of the study. A 10cm2 system (designed to deliver nicotine base at 72 μg/cm2/h) was applied for 24 h. Serial blood samples were taken at frequent intervals during dosing and after system removal. After a median 6 h lag time, nicotine plasma levels reached an average peak level of 15.2 ng/ml at a median peak time of 24 h. Following removal of the system, nicotine levels remained relatively constant for 1 h and then declined gradually. The half life was estimated as 4.0 h and the AUC(0–34 h) averaged 256.8 ng-h/ml. Prior to system application, the mean cotinine plasma level started at 214.5 ng/ml, and declined during application for 8 h before increasing to 186.7 ng/ml, 30 min after system removal. The average amount of nicotine delivered per system, as estimated by the residual nicotine content in the system, was 15 mg. The in vivo absorption of nicotine, after adjustment for the expected lag time, parallels the in vitro release as estimated by Wagner-Nelson analysis.

A small animal model utilizing salivary drug excretion for pharmacokinetic determinations

Abstract The use of small laboratory animals for pharmacologic research is well established. The need for more and varied information demands extensive data from these small animal experiments. Pharmacokinetic investigations, in particular, require frequent sampling of various biological fluids for drug level information. Such multiple/sequential sample collection has heretofore been possible only in larger animals and humans. The method presented here allows sequential collection of whole blood, parotid saliva, and cardiovascular information in a small animal model. Furthermore, this study demonstrates the usefulness of such a model for investigating drug interactions resulting from competition at plasma protein binding sites. Male Wistar rats received pentobarbital anesthesia and underwent a surgical procedure to facilitate stimulation and collection of parotid salivary secretions. Saliva and simultaneously collected whole blood samples were analyzed for pentobarbital content in the presence and absence of phenylbutazone, a highly competitive protein binding agent. In addition, arterial blood pressure was monitored to determine the effects of such drug displacement interactions on the cardiovascular system. Results indicate that pentobarbital levels in plasma decrease, while levels in saliva increase, following intravenous infusion of phenylbutazone. This effect was attributed to a displacement of pentobarbital from plasma protein binding sites by the more highly bound phenylbutazone. This shift in drug concentration correlated well with depressions in arterial blood pressure noted after phenylbutazone administration. It is apparent from these findings that phenylbutazone causes a relative increase in the free (nonprotein bound) levels of pentobarbital in plasma that are immediately available for transport to peripheral tissues, including the salivary glands and the central nervous system, where it depresses cardiovascular tone. We believe that this model provides a reliable mechanism for the study of a variety of problems that require multiple and/or sequential sampling of biological fluids in small animals. Additionally, this method is particularly useful in investigations requiring cardiovascular data to supplement drug level information. Possible applications of our method include bioassay and bioavailability studies of cardiotonic drugs, pressor and depressor agents. Of special interest is the ability of this method to elucidate mechanisms of drug interactions in vivo as demonstrated in our experiment.