Investigation of human pharmacoscintigraphic behavior of two tablets and a capsule formulation of a high dose, poorly water soluble/highly permeable drug (efavirenz).

Human pharmacoscintigraphic behavior of two tablets and a capsule formulation of a high dose, poorly water soluble, highly permeable, micronized drug (efavirenz) was investigated. The tablets and capsule, prepared with samarium oxide and neutron activated to produce radioactive samarium-153, were evaluated for their in vivo disintegration and gastrointestinal (GI) transit in healthy subjects under fasted condition. Scintigraphic images were acquired to coincide with blood sampling times to assess the plasma concentration-time profile in relation to in vivo disintegration and GI transit. The mean gastric emptying times were approximately the same for all three formulations. Although in vivo dosage form disintegration was faster for Tablet A as compared to Tablet B and was similar between Tablet A and the capsule, Tablet A showed a slower rate and extent of drug absorption than Tablet B and the capsule. The results of this study eliminated the initial hypothesis that the difference in in vivo performance between the two tablet formulations is due to a different rate of in vivo disintegration and suggest that for this drug the in vivo dissolution rate of the drug from its disintegrated dosage form was a more important factor affecting the rate and extent of drug absorption.

Pharmacokinetic interactions of moricizine and diltiazem in healthy volunteers.

Sixteen healthy male volunteers completed a nonrandomized, sequential, three-phase study. The three phases were 1) moricizine at 250 mg every 8 hours for 7 days with 12 days washout; 2) diltiazem at 60 mg every 8 hours for 7 days; and 3) concomitant administration of moricizine at 250 mg and diltiazem at 60 mg every 8 hours for 7 days. The plasma concentration-time profiles were obtained at the end of each phase for moricizine, diltiazem (with its metabolites desacetyl-diltiazem and N-desmethyl-diltiazem), and both when administered together. Under steady-state conditions, there was a two-way (opposing) pharmacokinetic drug interaction when moricizine and diltiazem were coadministered in healthy volunteers. Both maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve from time 0 to the end of administration (AUC tau) of moricizine increased significantly by 88.9% and 121.1%, respectively. Oral clearance (Clo) decreased by 54%. The terminal half-life (t1/2) of moricizine was not affected, however (2.1 +/- 0.5 hours versus 2.4 +/- 0.7 hours). It is believed that these changes were due to the inhibition of hepatic metabolism by diltiazem, which resulted in an increased systemic availability of moricizine. Moricizine had opposite effects on the pharmacokinetics of diltiazem. Moricizine decreased the Cmax of diltiazem significantly (by 36%) and increased Clo by 52%. A small but statistically significant decrease in the t1/2 from 4.6 +/- 1.3 hours to 3.6 +/- 0.7 hours was observed. Despite this result, no remarkable changes (e.g., in Cmax, AUC, or t1/2) were found for the two major diltiazem metabolites desacetyl-diltiazem and N-desmethyl-diltiazem. It appears that the pharmacokinetic interaction of moricizine and diltiazem was metabolic. With the increase in moricizine concentrations and the decrease in diltiazem concentrations, adjustments in dose may be required to achieve optimal therapeutic response when coadministering both agents.

Dose-dependent pharmacokinetics of warfarin in healthy volunteers.

PURPOSE: To examine the pharmacokinetics of warfarin after administration of single oral doses (2, 5, and 10 mg) to healthy male volunteers. METHODS: A sensitive reverse-phase HPLC method was used to quantify warfarin plasma concentrations as low as 6 ng/ml. Blood samples were collected for up to 120 hours following administration of these doses. RESULTS: As the dose decreased from 5 to 2 mg, the apparent volume of distribution (V/F) increased from 12 to 21 liters and the terminal half-life (t1/2) increased from 47 to 71 hours. Oral clearance remained unchanged over the examined dose range. These apparent dose-dependent changes in warfarin's t1/2 and V/F may be due to saturable tissue binding of this drug. It appears that a previously undetected and prolonged terminal phase may exist but can not be adequately characterized with the 120-hour sampling interval. To evaluate this long t1/2, a follow-up study was conducted to examine warfarin's pharmacokinetics for up to 21 days following a 10-mg dose. The prolonged terminal phase started to become apparent when plasma levels declined to less than 100 ng/ml. The t1/2 of this terminal phase was determined to be approximately one week. CONCLUSIONS: This is the first report that documents the dose-dependent pharmacokinetics of warfarin and the previously unreported long t1/2 of one week for warfarin in humans.

Variability in the pharmacokinetics and pharmacodynamics of low dose aspirin in healthy male volunteers.

Data describing the pharmacokinetics and pharmacodynamics of low dose aspirin (acetylsalicylic acid; ASA) are limited. This single-center study was designed to determine the rate and extent of oral absorption of 80-mg ASA tablets in healthy, young male subjects and to assess the intra- and inter-subject variability of ASA pharmacokinetics and platelet aggregation effects. Ten subjects each received a single, open-label, oral 80-mg ASA dose on three separate days. Each dose was separated by a 2-week washout interval. Blood samples for pharmacokinetic determinations of ASA and its metabolite, salicylic acid (SA) and platelet aggregation studies were obtained at scheduled timepoints before and up to 24 hours after each dose. Peak plasma ASA levels of 1 microgram/mL were achieved within 30 minutes. Peak plasma SA levels of approximately 4 micrograms/mL were attained in 1 hour. The terminal half-lives (t1/2) of ASA and SA were 0.4 and 2.1 hours, respectively. Both ASA and SA pharmacokinetics and the platelet aggregation response to ASA exhibited considerable intra- and inter-subject variability. Inhibition of platelet aggregation was found to relate with ASA area under the plasma concentration versus time curve (AUC).

Enzyme induction by moricizine: time course and extent in healthy subjects.

Moricizine.HCl, a novel phenothiazine derivative with oral antiarrhythmic activity, was examined for its potential to induce its own hepatic metabolism and to alter the pharmacokinetics of the test substrate, antipyrine, in 12 healthy male subjects. Antipyrine oral clearance increased from a starting value of .74 mL/minute/kg to .98 (+32%, P < .01) after 7 days of moricizine administration (250 mg every 8 hours) and to 1.15 mL/minute/kg after 14 days (+47%, P < .05); t1/2 was correspondingly reduced. Moricizine oral clearance increased from a baseline of 3.01 L/hour/kg to 3.62 (+20%, P < .05) after 6 days of oral moricizine and 4.66 (+51%, not significant) after 13 days. Moricizine t1/2 was marginally, but consistently, increased (+23%, P < .05) instead of decreased as one would expect because of enzyme induction, presumably due to a decrease in systemic bioavailability and its influence on the oral volume of distribution. In half of the subjects who discontinued moricizine after 7 days, antipyrine pharmacokinetic values returned to near baseline 7 days later. Although moricizine was able to induce its own hepatic metabolism and that of antipyrine after 6 or 7 days of continuous administration, the electrocardiographic properties of moricizine did not appear to be altered by continuous dosing.

Effect of moricizine on the pharmacokinetics of single-dose theophylline in healthy subjects.

We studied the effect of multiple oral doses of moricizine on the pharmacokinetics of theophylline in healthy male subjects. Twelve subjects initially received two single oral doses of theophylline, one in the form of immediate-release Aminophyllin on day 1 and the other in the form of controlled-release Theo-Dur on day 3. Multiple oral doses of moricizine (Ethmozine, 250 mg every 8 h) began on day 5 and continued for 18 days. While receiving moricizine, the subjects were again given the two formulations of theophylline in the same order on days 19 and 21. Theophylline pharmacokinetic profiles were obtained over 36 h after all theophylline administrations. Multiple-dose moricizine administration significantly decreased (p < 0.0005) theophylline area under the curve by 32 and 36% after Aminophyllin and Theo-Dur, respectively. Theophylline t1/2 was also significantly decreased (p < 0.02) by concomitant moricizine dosing. Moricizine had no apparent effect on theophylline absorption after Aminophyllin, based on the lack of changes in the maximum plasma concentration (Cmax) and the time to reach Cmax; however, moricizine administration did decrease (p < 0.0005) the Cmax of theophylline after Theo-Dur. We conclude that these pharmacokinetic changes are most likely due to enzyme induction mediated by moricizine. Consequently, concomitant use of moricizine and theophylline may necessitate the administration of more frequent and higher doses of theophylline.

Effect of moricizine on the pharmacokinetics and pharmacodynamics of warfarin in healthy volunteers.

Moricizine HCl, a new orally active antiarrhythmic agent, induces its own hepatic metabolism and consequently may interfere with the metabolism of warfarin, a drug used commonly by cardiac patients that also is subject to extensive hepatic metabolism. Both drugs are also highly protein bound in plasma. To assess the possibility of an interaction, single-dose sodium warfarin (25 mg oral Coumadin, Du Pont Pharmaceuticals, Wilmington, DE) pharmacokinetics, pharmacodynamics; and plasma protein binding were examined in 12 healthy male volunteers 14 days before and 14 days after starting chronic oral moricizine HCl administration (250 mg every 8 hours). The terminal elimination rate constant of warfarin was increased by about 10% when measured in the presence of chronic moricizine administration. However, oral plasma clearance, apparent volume of distribution, maximum peak plasma concentration, time to reach peak concentration, and protein binding were unaffected. More importantly, there was no evidence of a pharmacodynamic interaction based on the prothrombin time profile. It was concluded that no clinically significant interaction occurs under these conditions.

Dose proportionality of moricizine after escalating multiple doses in healthy volunteers.

This study was designed to determine the dose linearity and proportionality of moricizine after multiple-dose administrations of 450 to 900 mg/day. The study design was an open-label, four-treatment, four-period sequentials escalating dose. Twelve subjects each received multiple doses of 150, 200, 250, and 300 mg of moricizine every 8 hours during 7 days of treatment. Blood samples for pharmacokinetic determinations were obtained on day 7 of each treatment period during an 8-hour time interval. Cmin determinations were also made on specific days of each treatment period. The AUC tau (area under the curve from time 0 to 8 hours), Cmax, and Cmin parameters were all normalized to the 250-mg (750 mg/day) dose. No statistically significant differences were seen in these parameters at the four treatment levels. It was concluded that moricizine follows first-order or linear pharmacokinetics after multiple dosing and exhibits dose proportional pharmacokinetics in the dosage-range studies. This range corresponds to the clinically useful dosage range.

Altered drug-serum protein binding in the genetically obese Zucker rat.

Drug-serum protein binding was evaluated in genetically obese Zucker rats, their lean littermates, and lean Sprague-Dawley rats. The free fraction (fp) of phenytoin was significantly higher in the obese rat (fp = 0.177) compared to its lean littermate (fp = 0.136), apparently due to displacement by free fatty acids. Conversely, diazepam and propranolol fp values were decreased in the obese Zucker rat (fp = 0.107 and fp = 0.122, respectively) compared to the lean Zucker rat (fp = 0.140 and fp = 0.174, respectively). Evidence strongly suggests that the increased binding of propranolol was not due to elevations in the serum concentrations of alpha1-acid glycoprotein (as is the case in the human obese population). Rather, the decreased fp for both diazepam and propranolol was a result of increased lipoprotein partitioning. Strain differences between the lean Zucker rat and lean Sprague-Dawley rat were also evident, with serum binding of the Sprague-Dawley rat more closely resembling the obese Zucker rat.

Serum protein binding and the role of increased alpha 1-acid glycoprotein in moderately obese male subjects.

Serum protein and lipid concentrations as well as the serum protein binding of propranolol, diazepam and phenytoin were measured in normal weight and obese volunteers. Concentrations of alpha 1-acid glycoprotein (AAG) in the obese subjects were double that of the lean controls. Conversely, concentrations of high density lipoproteins (HDL) were decreased in the obese group. The serum binding of propranolol was increased in the obese subjects and correlated with serum AAG concentrations. Diazepam binding was slightly decreased in the obese as a result of lower serum albumin concentrations and elevated free fatty acids. The binding of phenytoin was comparable in all of the volunteers. These findings point out some of the complex pathophysiologic changes associated with obesity which may in turn influence drug disposition and hence drug therapy in the obese patient.

Physiological model for distribution of sulfathiazole in swine.

A physiological flow model was developed for the distribution of sulfathiazole residues in various tissues in swine. The approach was compartmental, in which the compartments and equilibrium constants had physiological meaning. Differential equations were developed, and appropriate parameter values and initial conditions were substituted and solved by a fourth-order Runga-Kutta technique. Simulation values corresponded with the experimentally determined concentration values in plasma and kidney, liver, muscle, fat, and heart tissues.

Influence of smoking on serum protein composition and the protein binding of drugs.

The influence of smoking an alpha 1-acid glycoprotein (alpha 1-AGP) and serum albumin concentrations and the protein binding of phenytoin and propranolol in healthy volunteers was investigated. alpha 1-AGP concentrations were found to be statistically different (P less than 0.05) in the smokers (mean = 84.3 mg dl-1) versus non-smokers (mean = 62.8 mg dl-1). There was a trend for lower serum albumin concentrations and lower fraction unbound of propranolol in the smokers. Smoking did not affect the protein binding of phenytoin.

Serum alpha 1-acid glycoprotein and the binding of drugs in obesity.

Although clinically relevant, drug-protein interactions in the morbidly obese population have not been studied thoroughly. The objective of this study was to evaluate serum chemistry profiles and the degree of serum protein binding of propranolol, diazepam and phenytoin in the serum of four female, morbidly obese (greater than 190% of ideal body weight) and eight control female subjects. Serum triglyceride concentrations were higher and high-density lipoproteins were lower in the obese subjects than in the control group. Serum albumin and total protein concentrations in the obese were not different from controls. Unexpectedly, alpha 1-acid glycoprotein concentrations were doubled in the obese subjects (mean obese value 121 mg/100 ml vs 62.9 mg/100 ml for the control subjects). Obese subjects had a mean fraction unbound (fu) for propranolol of 0.086, which was significantly different from the controls (fu = 0.123). The binding of diazepam was decreased slightly in the obese subjects. The binding of phenytoin was similar in both groups. The altered serum chemistry of obesity may play a significant role in the drug management of the obese patient by altering drug-protein interactions.