Effect of renal impairment on the pharmacokinetics and pharmacodynamics of desirudin.

OBJECTIVE: To investigate the pharmacokinetics and pharmacodynamics of desirudin in subjects with various degrees of renal impairment in comparison with subjects with normal renal function. METHODS: Eight subjects with normal renal function (creatinine clearance > 90 ml/min) received 0.5 mg/kg desirudin intravenously over 30 minutes. Four subjects with mild renal failure (creatinine clearance between 61 and 90 ml/min) received 0.5 mg/kg. Five subjects with moderate renal failure (creatinine clearance between 31 and 60 ml/min) received 0.25 mg/kg. Six subjects with severe renal failure (creatinine clearance < 31 ml/min) received 0.125 mg/kg. RESULTS: Specific maximum concentration values (maximum concentrations corrected to a dose of 1 mg/kg) increased slightly with decreasing creatinine clearance. Mean specific area under the plasma concentration-time curve increased by a factor of 1.15, 2.83, and 7.0 for subjects with mild, moderate, and severe renal failure, respectively, compared with healthy subjects. Total urinary excretion of desirudin was about 55% to 60% of the dose in all four groups; elimination was delayed for subjects with moderate and severe renal failure. Total and renal clearance of desirudin were proportional to creatinine clearance. Total plasma clearance of desirudin was proportional to renal clearance of the drug. Prolongation of activated partial thromboplastin time was increased among subjects with moderate and severe renal failure despite a dose reduction. Area under the dynamic activated partial thromboplastin time curve for subjects with moderate renal failure remained the same as that for healthy subjects despite a dose reduction by a factor of two. Area under the dynamic curve increased by a factor of about 1.5 for subjects with severe renal failure despite a dose reduction by a factor of four. CONCLUSION: A dose reduction by a factor of six is recommended for persons with severe renal failure.

Uricosuric effect of CGS-12970, a new thromboxane synthase inhibitor.

3-Methyl-2-(3-pyridyl)-1-indoleoctanoic acid (CGS-12970) is a reversible thromboxane synthase inhibitor that was noted to lower serum uric acid during preliminary trials in humans. Our clinical research unit studied 20 healthy male volunteers who received two doses of CGS-12970 12 hours apart (100, 200, 300, or 400 mg twice a day). Four subjects received placebo as a control. Serum uric acid concentrations decreased between 34% and 47%. Urinary excretion of uric acid increased between 28% and 134% within 12 hours of the first dose. Urinary excretion of uric acid returned to baseline within 24 hours after the last dose. In vitro study of bovine-creme xanthine oxidase inhibitor activity revealed minimal inhibition of xanthine oxidase by either CGS-12970 or its metabolite, CGS-12961. CGS-12970 appears to be a potent reversible uricosuric agent. We hypothesize that the uricosuric effect may be attributable to the acidic properties of CGS-12970 rather than to its inhibition of thromboxane synthase.

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 x 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.

Inhibition of angiotensin-converting enzyme with libenzapril in normotensive males.

The effect of intravenous (i.v.) libenzapril was studied in six healthy males by administering i.v. angiotensin I (AI) administered in stepwise increments of 20 ng/kg/5 min until the subjects' systolic blood pressure (SBP) had increased 20-30 mm Hg above baseline. The mean baseline infusion of 63 ng/kg/5 min resulted in a significant (P < 0.05) increase in the ratio of AII to AI plasma levels from 0.52 +/- 0.46 to 7.92 +/- 4.48 and a SBP increase of 120 +/- 7.1 to 147 +/- 5.6. Within 15 minutes of starting the 1-mg infusion of libenzapril over 1.5 hours, the AII/AI ratio decreased to baseline values, and the SBP had returned to baseline in 1 hour. Repeat AI challenges at 3.5 and 5 hours postdose did not increase SBP significantly. Even the 6.5-hour challenge demonstrated only a slight increase in SBP, with an AII/AI ratio of 0.26. At 24 hours, SBP was only 40% of the baseline response, demonstrating that libenzapril is a potent long-acting ACE inhibitor.

Hypoglycemic and insulin response to a continuous intravenous infusion of CGP-35126 recombinant human insulin-like growth factor-I (rhIGF-I) in healthy males.

Recombinant human insulin-like growth factor-I (rhIGF-I) produced by expression in a yeast vector was evaluated in seven normal men to determine effects on plasma glucose and insulin levels. Each subject received an initial intravenous infusion of normal saline and on the following day, rhIGF-I at a rate of 21.4 micrograms/kg/hour. Each infusion lasted for 7 hours. The subjects' fasting baseline glucose and insulin levels were not statistically different (P > .05) from their pre-dose levels. Compared with the saline (control) infusion, serum glucose levels were statistically lower (P < .05) 2 hours into the rhIGF-I infusion. These lower glucose levels were maintained until the subjects consumed a standard lunch (4 hours into the infusion). Insulin levels demonstrated a similar response to rhIGF-I, but decreases in insulin levels occurred after the rhIGF-I hypoglycemic effect. This observation suggests that suppression of insulin levels may be due to secondary hypoglycemia rather than to a direct rhIGF-I effect. This study demonstrated the desired rhIGF-I effect of lowering subjects' glucose levels without clinically significant hypoglycemia. This finding suggests that rhIGF-I may have potential clinical utility in hyperglycemic states.

Excretion of barbiturates into induced parotid saliva of the rat.

On the basis of the results presented in this study, it has been shown that the five barbiturates studied are excreted into the parotid saliva of the rat. Furthermore, it has been shown that the salivary excretion of these agents, as indicated by their S/P concentration ratios can be correlated with the lipid solubility as indicated by the L/W partition coefficient, and can be correlated to a lesser extent with the degree of drug ionization and plasma protein binding.

Secretion of drugs by the parotid glands of rats and human beings.

The following drugs have been demonstrated to be secreted by the parotid glands of rats and human beings: amobarbital, chlorpromazine, codeine, glutethimide, meprobamate, pentobarbital, phenobarbital, and secobarbital. Methadone could not be detected in the parotid saliva of either rats or human beings, and morphine has been demonstrated only in parotid saliva of rats.

Correlations of parotid saliva and plasma lidocaine concentrations in rats.

The concentration ratios of parotid saliva to plasma lidocaine were determined in rats after a single dose (10 mg of lidocaine/kg) and constant infusion (60 micrograms of lidocaine/kg/min). Parotid saliva and plasma samples were obtained at 10, 20, and 30 min after single-dose lidocaine administration and at 70, 80, and 90 min after the initiation of a lidocaine infusion. The saliva/plasma concentration ratios for lidocaine after single-dose administration decreased from 1.13 +/- 0.03 at 10 min to 0.51 +/- 0.06 at 30 min, whereas the ratios determined during the lidocaine infusion remained constant (0.43 +/- 0.03, 0.45 +/- 0.03, and 0.43 +/- 0.04) over the time period tested. The variable saliva/plasma concentration ratios obtained after single-dose administration may be associated with rapid drug distribution between the plasma and peripheral compartments and variation in lidocaine binding to plasma proteins. However, during constant lidocaine infusion, a steady-state concentration was achieved within 70 min, as demonstrated by the constant saliva/plasma concentration ratios.

5-Fluorouracil concentrations in rat plasma, parotid saliva, and bile and protein binding in rat plasma.

The pharmacokinetics of 5-fluorouracil were studied over a 60-min period in rats that received 12.5, 25.0, and 50.0 mg/kg iv. The plasma concentration-time relationship and the detectability in bile and parotid saliva (a route of elimination heretofore given little or no attention) were examined. Protein binding of 5-fluorouracil at concentrations chosen to approximate those found in plasma was determined by equilibrium dialysis. Bile-plasma and parotid saliva-plasma concentration ratios were calculated. 5-Fluorouracil concentrations were quantitated by high-performance liquid chromatography. Plasma concentrations at all doses studied appeared to rapidly decline. The half-life, however, at the 50.0-mg/kg dose (27 min) was significantly longer (p less than 0.025) than the corresponding half-life at the 25.0-mg/kg dose (22 min). This may be attributed to an easily saturable hepatic degradation. Although an observed decline in bile-plasma and parotid saliva-plasma concentration ratios at higher doses may represent saturation of these excretary routes, the small amounts of 5-fluorouracil detected in bile and parotid saliva probably contribute negligibly to the elimination of the total drug equivalents administered. Parotid saliva-plasma concentration ratios were not useful in predicting plasma protein binding as determined by equilibrium dialysis. Excretion of intravenously administered 5-fluorouracil in saliva, however, exposes the upper GI tract to this agent and may play a part in causing stomatitis in patients receiving the drug by this route.

Investigation of digoxin, quinidine, and disopyramide interactions in rats utilizing parotid saliva, blood, and other tissues.

Blood, parotid saliva, heart, liver, and kidney concentrations of digoxin and quinidine were determined in rats chronically treated with digoxin and in nontreated (control) rats after the administration of quinidine (20 mg/kg ip) and disopyramide (10 mg/kg ip). The results indicated that digoxin concentrations increased significantly and proportionally in parotid saliva and plasma after quinidine, but did not increase after disopyramide. With the exception of the liver, which showed an increase in digoxin concentrations, tissue concentrations of digoxin did not differ from control animals. In rats pretreated chronically with digoxin, quinidine concentrations in plasma, parotid saliva, or heart tissue did not differ significantly from control animals, but were significantly lower than controls in liver and kidney tissues. The results presented here lend additional support to the hypothesis that the increase in digoxin plasma concentration following quinidine administration is primarily due to interference with renal excretion and displacement of digoxin by quinidine binding sites. Furthermore, its was demonstrated that disopyramide has little or no effect on plasma digoxin levels in rats.

Prolonged hyperalimentation in catabolic chronic dialysis therapy patients.

Plasma concentrations of 25 essential (EAA) and nonessential (NEAA) amino acids were measured pre- and postdialysis in 46 chronic hemodialysis therapy (CDT) patients. Sixteen of these patients with prior weight loss of 14.5 +/- 2.37 pounds in 24 months were administered a GAA solution (EAA + NEAA + glucose) for 20 weeks during each dialysis. Eight of these patients (group 1) responded with improved appetite and weight gain; the remaining eight patients (group 2) with clinically advanced metabolic bone disease continued to lose weight. Five other patients (group 14), biochemically similar to group 1 but with shorter prior dialysis experience, who received EAA (plus glucose) hyperalimentation (including oral I-histidine), experienced weight gain similar to group 1 but displayed significantly different plasma aminograms indicating a deficit of NEAA. When EAA and glucose hyperalimentation was administered without histidine (1 patient) no weight gain occurred and aminograms differed significantly from other groups. Plasma aminograms of 25 weight-stable, nonhyperalimented CDT patients were obtained for comparison. Results indicate GAA hyperalimentation can promote weight gain in catabolic CDT patients with inadequate prior nutritional intake (as in groups 1 and 14) but cannot reverse weight loss when the primary clinical setting is advanced metabolic bone disease and myopathy due to hyperparathyroidism (group 2). Hyperalimentation with glucose and an amino acid solution specifically tailored to the needs of CDT patients may improve results. Plasma phosphoethanolamine levels, normal for weight-stable and elevated in catabolic CDT patients, suggest a possible role for phosphoethanolamine as a marker for catabolism.

Pharmacodynamics of a continuous intravenous infusion of CGP-35126 recombinant human insulin-like growth factor-I (rhIGF-I) on glucose and insulin levels in healthy males.

Recombinant human insulin-like growth factor-I (rhIGF-I) was evaluated in 7 healthy males to determine the pharmacodynamics on glucose and insulin levels. Each subject received an initial intravenous infusion of normal saline and on the following day, rhIGF-I at a rate of 21.4 micrograms/kg/h over 7 hours. The subjects' fasting baseline glucose and insulin levels were not statistically different (p > 0.05) from their pre-dose levels. Compared to the saline (control) infusion, glucose levels were statistically lower (p < 0.05) 2 hours into the rhIGF-I infusion, and were suppressed until the subjects consumed a standard lunch (4 hours into the infusion). Insulin levels demonstrated a similar response to rhIGF-I, but decreases in insulin levels occurred after the rhIGF-I hypoglycemic effect. Therefore, suppression of insulin levels may be due to hypoglycemia rather than a direct action of rhIGF-I. This trial demonstrated the desired rhIGF-I effect of lowering subjects' glucose levels without clinically significant hypoglycemia. This finding suggests that rhIGF-I may have potential clinical utility in hyperglycemic or insulin resistant states.

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.

Doxorubicin and 5-fluorouracil plasma concentrations and detectability in parotid saliva.

Doxorubicin and 5-fluorouracil pharmacokinetics were studied in 19 volunteers with various advanced neoplastic diseases who received 50-90 mg doxorubicin or 600-1000 mg 5-fluorouracil intravenously, followed by plasma and parotid saliva collection over a 75 min period. The extent to which these chemotherapeutic agents are bound to plasma proteins, at concentrations chosen to approximate plasma concentrations, was measured by equilibrium dialysis. Both agents were quantitated by high-performance liquid chromatography. As reported previously, a wide range of plasma levels were found among patients receiving similar doses of either doxorubicin or 5-fluorouracil. It appears that in addition to being quickly cleared from the plasma both chemotherapeutic agents are excreted in detectable amounts in parotid saliva, a route of elimination heretofore given little or no attention. Excretion in the saliva exposes the mucosa of the upper gastrointestinal tract to 5-fluorouracil after intravenous administration and may play a part in causing stomatitis in patients receiving it by this route. Since there are huge interindividual and pronounced intraindividual differences in S/P ratios mostly not systematically related to the drugs' concentration in plasma, the concentration in parotid saliva was not useful in predicting the level of free doxorubicin or 5-fluorouracil in plasma.

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.

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 micrograms/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.