Transmucosal, oral controlled-release, and transdermal drug administration in human subjects: a crossover study with melatonin.

The effect of oral controlled-release (CR), oral transmucosal (buccal; TMD) and transdermal (TDD) drug delivery systems on plasma concentrations of melatonin (MT) and its principal metabolite in human subjects using a crossover, single dose design was evaluated. Twelve adult male volunteers participated in the study and received all three dosage forms on three separate occasions. All patch dosage forms were removed after 10 h of wear. Plasma concentrations of the parent drug and its metabolite, 6-sulfatoxymelatonin (MT6s) were measured by radioimmunoassay. Between-subject plasma concentrations of MT were very variable following both oral CR and TDD. Use of the oral CR system gave plasma MT profiles in some subjects that were initially similar to physiological levels, but then differed substantially from physiological in the rate of MT offset; in a few subjects, plasma MT levels remained consistently much below normal nocturnal physiological levels. Also, the ratio of metabolite to parent drug by the oral CR route was many times greater than physiological. TDD resulted in a significant delay in systemic drug levels and a gradual decline in drug delivery after patch removal, possibly due to deposition of melatonin in the skin. TDD failed to simulate the physiological plasma profile of MT (rapid achievement of steady-state blood levels and rapid decline after removal of the patch; i.e., so-called "square-wave" profile). TMD provided prompt systemic drug levels with less variability than oral CR or TDD delivery. Also, plasma MT levels fell promptly and rapidly after removal of the patch. No indication of mucosal deposition was observed. TMD was able to mimic the physiological plasma profiles of both MT and its principal metabolite.

Flecainide excretion in human breast milk.

Healthy human volunteers who intended not to breast feed were placed on a regimen of 100 mg oral flecainide every 12 hours for 5 1/2 days beginning 1 day after parturition. Milk and blood samples were collected during the dosing period and for 2 days after the last dose. Concentrations of flecainide in milk and plasma were assayed by HPLC. Apparent steady-state levels of flecainide in both milk and plasma were achieved in most cases by day 4 of the study. Highest daily average concentration of flecainide in milk ranged from 270 to 1529 ng/ml for the 11 subjects. Mean +/- SD milk to plasma flecainide ratios were 3.7 +/- 3.5, 3.2 +/- 2.3, 3.5 +/- 2.1, and 2.6 +/- 0.7 on study days 2, 3, 4, and 5, respectively. After the last dose of flecainide, peak milk levels of the drug occurred at 3 to 6 hours and then declined monoexponentially. The half-life for elimination of flecainide from milk was 14.7 +/- 3.5 hours and is very similar to the plasma elimination half-life of flecainide in healthy human subjects. The mean milk to plasma ratios for flecainide after the last dose were 2.3 +/- 1.0 and 2.9 +/- 1.1 at 24 and 48 hours after the dose, respectively. Based on the pharmacokinetics of flecainide in infants, the expected average steady-state plasma concentration of flecainide in a newborn infant consuming all of the milk production of its mother (approximately 700 ml/day) would not be expected to exceed about 62 ng/ml.(ABSTRACT TRUNCATED AT 250 WORDS)

The pharmacodynamic and pharmacokinetic interaction between single doses of flecainide acetate and verapamil: effects on cardiac function and drug clearance.

Flecainide and verapamil are antiarrhythmic agents that may be used in combination. We have examined their pharmacodynamic interaction by M-mode echocardiography and electrocardiography in eight normal male volunteers (24 +/- 1.8 years of age). Flecainide decreased the left ventricular ejection fraction (LVEF) (-4.4 +/- 1.2%, p less than 0.008), but verapamil did not. Neither drug affected cardiac output or vascular resistance. Both drugs increased the PR interval (12 +/- 4 msec, p less than 0.01 for flecainide; 12 +/- 5, p less than 0.04 for verapamil). Flecainide, but not verapamil, increased the QTc interval (23 +/- 8 msec, p less than 0.02). Both drugs also increased the systolic time interval ratio (PEPc/LVETc) (0.074 +/- 0.012, p less than 0.0004 for flecainide; 0.029 +/- 0.008, p less than 0.007 for verapamil). The combination of flecainide and verapamil had additive effects on myocardial contractility and on atrioventricular conduction. Verapamil slightly decreased the plasma clearance of flecainide (7.78 +/- 0.60 ml/kg/min for flecainide alone, 7.34 +/- 0.48 ml/kg/min for flecainide and verapamil together, p less than 0.05). On the other hand, flecainide had no effect on the plasma clearance of verapamil, which suggests that there was little interaction between the two drugs on their pharmacokinetic parameters.

Flecainide acetate for resistant arrhythmias in the young: efficacy and pharmacokinetics.

Drug efficacy and pharmacokinetics were assessed in 63 patients, aged 5 days to 30 years (mean 8 years), who received flecainide acetate for control of resistant arrhythmias. Doses of flecainide ranged from 59 to 225 mg/m2 body surface area per day (mean 141) in divided doses every 8 to 12 h and serum trough levels ranged from 0.10 to 0.99 micrograms/ml (mean 0.36). Flecainide controlled or partially controlled arrhythmia in 53 (84%) of the 63 patients: 7 of 7 patients who had the permanent form of junctional reciprocating tachycardia, 12 of 13 who had an atrial ectopic tachycardia, 10 of 10 who had ventricular tachycardia and 18 of 25 patients who had reentrant supraventricular tachycardia. Five of seven patients who had the latter arrhythmia were unsuccessfully treated with flecainide. They had Wolff-Parkinson-White syndrome and developed asymptomatic, incessant, slower orthodromic reciprocating tachycardia while receiving the drug. Transient blurred vision was reported in three patients and two patients had transient hyperactivity. No significant hemodynamic side effects were seen in any patient. Twenty-five patients underwent oral pharmacokinetic investigation. Young infants (less than 1 year of age) had a mean plasma elimination half-life (t 1/2) approximating that (11 to 12 h) found in older children and healthy adults; children aged 1 to 12 years had a shorter mean t 1/2 of 8 h. Dosing schedules based on milligrams per square meter body surface area correlated better with plasma flecainide levels than did dosing based on milligrams per kilogram body weight.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of flecainide in patients with cirrhosis of the liver.

The pharmacokinetics of flecainide were studied in six patients with cirrhosis of the liver and in six healthy subjects after a single 2 mg/kg intravenous dose. Hepatic biotransformation capability before flecainide dosing was assessed by antipyrine challenge. The mean plasma antipyrine t1/2 for patients (42.2 hours) was longer (p less than 0.01) than that for subjects (11.7 hours). For control subjects, the plasma t1/2 of flecainide (9.5 hours) was shorter (p less than 0.01), plasma clearance (9.1 ml/min/kg) was faster (p less than 0.01), and volume of distribution (7.5 L/kg) was smaller (p less than 0.05) compared with corresponding values in patients. Renal clearance did not differ (p greater than 0.05) between the two groups. The mean ratio of renal clearance to plasma clearance for subjects (0.4) was smaller (p less than 0.05) than that for patients. The slower rate of flecainide elimination from plasma in patients is likely due to reduced hepatic biotransformation. In patients with cirrhosis, plasma levels of flecainide may accumulate to unacceptably high levels with usual dosage regimens.

Flecainide acetate does not alter the energy requirements for direct ventricular defibrillation using sequential pulse defibrillation in pigs.

Flecainide acetate is a recently approved class 1c antiarrhythmic agent indicated for patients with serious ventricular arrhythmias. Because flecainide may be used in patients with automatic implantable defibrillators, we assessed the effect of flecainide on ventricular defibrillation energy requirements in a pig model. Different doses of flecainide maintaining plasma levels in the "subtherapeutic" (six pigs), "therapeutic" (eight pigs), and "supratherapeutic" (eight pigs) range were administered to three groups of pigs. A fourth group (six pigs) served as a time control and was given normal saline only. Episodes of ventricular fibrillation were induced and then terminated using sequential truncated trapezoidal direct current shocks delivered by a tripolar internal defibrillator system. Energy requirements for defibrillation were assessed by measuring defibrillation threshold and also by comparing shifts in the curves relating energy with percent successful defibrillation. Flecainide failed to alter defibrillation requirements at any dose. We conclude that ventricular defibrillation energy requirements are not affected by flecainide in our pig model. Both the defibrillation threshold technique and the comparison of curves relating success of defibrillation to energy yielded similar results suggesting that either can be used to assess energy requirements for defibrillation.

Flecainide pharmacokinetics after multiple dosing in patients with impaired renal function.

STUDY OBJECTIVE: To determine the pharmacokinetics of oral flecainide acetate after single and multiple doses in patients with impaired renal function. DESIGN: Paired study of single followed by multiple oral doses. SETTING: PATIENTS enrolled in a Veterans Administration Hospital renal subspecialty clinic and dialysis unit. PATIENTS: Twenty men and one woman between the ages of 33 and 74 years with impaired renal function including ten patients with end-stage renal disease receiving maintenance hemodialysis. INTERVENTIONS: All patients received a single, oral, 200-mg dose of flecainide acetate followed by sequential venous blood sampling. Seven to 14 days after the single-dose study, each patient received 100 mg of flecainide acetate by mouth every 12 hours or every 24 hours for 10 days. Venous blood samples were drawn periodically during multiple dosing and sequentially after the last dose. Measurements and primary results: Peak flecainide acetate concentrations (micrograms/L) were 330 +/- 104 micrograms/L (mean +/- SD) after the single dose and 687 +/- 505 micrograms/L after multiple doses. Time to peak occurred at 3.3 +/- 2.3 hours and 2.7 +/- 1.2 hours after single and multiple doses, respectively. The apparent volume of distribution was 8.2 +/- 2.9 L/kg and 9.2 +/- 5 L/kg after single and multiple dose studies, respectively. Plasma elimination half-life after the single dose (20.4 +/- 9.0 hours) was significantly shorter (P less than .001) than after multiple doses (37.8 +/- 39.7 hours), as was total body clearance: 391 +/- 154 mL/min versus 302 +/- 194 mL/min. There were no statistically significant differences between pharmacokinetic measurements determined for patients on chronic hemodialysis when compared with nondialysis patients during the multiple-dose study.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of flecainide acetate in patients with severe renal impairment.

We studied the effect of renal disease on the pharmacokinetics of flecainide after single intravenous, single oral, and multiple oral doses to patients with severe renal disease (creatinine clearances less than 12 ml/min/m2). The absorption and volume of distribution of flecainide were not altered by renal impairment. The average plasma half-life was prolonged by about twofold that of healthy subjects but most patients were within the range of values for healthy subjects. Total body clearance was reduced. With multiple oral doses of 50 mg b.i.d. or 50 mg daily, steady-state plasma levels were reached by 6 days and no further accumulation in plasma was observed. In patients with severe renal disease, therapy with flecainide should be initiated at 100 mg daily (or 50 mg b.i.d.). If necessary, dosage increases should be made cautiously at intervals of more than 4 days when plasma levels have plateaued as demonstrated by plasma level monitoring.

High-performance liquid chromatographic method for the quantitation of a meta-O-dealkylated metabolite of flecainide acetate, a new antiarrhythmic.

A simple, sensitive and selective high-performance liquid chromatographic method has been developed to analyze meta-O-dealkylated flecainide, a major metabolite of flecainide acetate, in human biological fluids. Sample preparation is accomplished through the use of bonded-phase extraction columns and the samples are chromatographed on a reversed-phase system with fluorescence detection. An external calibration method is used for quantitation and the inter-day and intra-day precision and accuracy are good. The method has been used to determine metabolite levels in samples from healthy subjects and patients with arrhythmias or renal impairment.

Biotransformation and elimination of 14C-flecainide acetate in humans.

The metabolism of 14C-flecainide acetate, a new antiarrhythmic, was investigated in four healthy human subjects, after a single, 200-mg oral dose. The cumulative recovery of radioactivity ranged from 81 to 90% (mean, 86%) in urine and from 4 to 6% (mean, 5%) in feces; thus, flecainide does not appear to undergo extensive biliary excretion, unless reabsorption occurs after biliary elimination. The cumulative excretion in urine of unchanged flecainide ranged from 35 to 50% (mean, 42%) of the dose and was essentially complete by 72 hr postdose. Peak plasma levels of radioactivity (524 to 848 ng eq/ml) and of unchanged flecainide (214 to 281 ng/ml) were attained at 2 to 3 hr postdose. The average half-life for the disappearance of unchanged flecainide from plasma was about 16 hr; disappearance of total metabolites from plasma was only slightly slower. Radiomonitored TLC analysis showed that urine contained two major metabolites and two or three minor ones; both major metabolites were extensively conjugated. By TLC, NMR, and mass spectral comparisons to reference compounds, the two major urinary metabolites were shown to be meta-O-dealkylated flecainide and the meta-O-dealkylated lactam of flecainide. Most of the radioactivity in urine was accounted for by flecainide and the two major metabolites.

Structure-activity relationship studies of phencyclidine derivatives in rats.

Phencyclidine (PCP), a semirigid molecule containing a cyclohexane ring with vicinally attached aromatic and piperidine rings, produces characteristic discriminative stimulus properties and pupillary miosis in rats. The effectiveness of a series of aromatic and nitrogen substituted analogs of PCP in producing PCP-like discriminative stimuli and changes in pupil diameter was determined in rats trained to discriminate between saline and 3.0 mg/kg of PCP. Dexoxadrol and its optical isomer levoxadrol were also evaluated for purposes of comparison. Analogs in which the electron-density of the aromatic ring was increased (3NH2-PCP) or only slightly reduced (3F-PCP) retained PCP-like activity. A loss of PCP-like activity occurred with analogs in which the electron-density of the aromatic ring was greatly reduced (3NO2-PCP) or extended to a larger system (1NCP and 2NCP). PCP-like activity also was abolished in analogs in which the distance between the aromatic ring and the remainder of the molecule was systematically increased by one, two or three methylene units. In contrast, substitutions on the nitrogen atom altered the potency, but not the efficacy, of such analogs. Dexoxadrol produced PCP-like activity whereas its optical enantiomer levoxadrol was devoid of such activity. These findings suggest a drug receptor surface with multiple domains or subsites which recognize regions of structural overlap among the phencyclidines, dioxolanes and psychotomimetic benzomorphan derivatives.

Effects of cycloalkyl ring analogs of phencyclidine on behavior in rodents.

The purpose of the present experiments was to evaluate the effects of eliminating or varying the size of the cycloalkyl ring of phencyclidine (PCP) from 3 to 8 carbons while leaving the composition of the benzene and piperidine rings unaltered. Compounds were evaluated for their effectiveness in producing PCP-like discriminative stimuli and changes in pupil diameter in the rat and impaired motor performance on the Rotarod in the mouse. All modifications of the cycloalkyl ring of PCP significantly reduced the relative potencies of the cycloalkyl analogs, shortened their duration of action and also modified their spectra of action, including their effectiveness in producing PCP-like discriminative stimuli and miosis in the rat as well as ataxia in the mouse. The present results demonstrate that the cyclohexyl moiety of PCP is an absolute requirement for producing a full PCP-like spectrum of activity.

Distribution of 13N in rat tissues following intravenous administration of nitroso-labeled BCNU.

The concentrations of label in 16 major organs and tissues of pentobarbital-sedated normal male rats were measured at six time points ranging from 0.2 to 50 min after IV injection of the antitumor drug BCNU labeled in the nitroso position with cyclotron-produced nitrogen-13. Initial (12-s) concentrations in the lungs, kidneys, and heart were 41, 13, and 11 times the whole-body average, respectively. Time for clearance of the first 50% of the injected dose from the circulation was of the order of several seconds. Estimated first-pass extractions of 70% or more were noted in the heart, kidneys, brain, stomach, small intestine, muscle, fat, and bone. Washout of label from the heart and lungs was quite rapid, removing most of the initially extracted 13N from these organs by 2 min after injection. Label concentrations in the kidneys exceeded those in all other tissues studied between 2 and 50 min. Secondary accumulations of 13N were observed in muscle, skin, liver, small intestine, and fat. Label concentrations in a number of tissues closely paralleled the steadily decreasing concentration in blood for various intervals between 5 and 50 min. The results suggest that the toxic insult to lung tissue from IV administered BCNU is effected in a period of several minutes. They also suggest that intra-arterial administration of the drug would significantly raise the target/non-target dose ratio and lower the incidence of pulmonary toxicity.

Structure-activity relationships of the cycloalkyl ring of phencyclidine.

In order to investigate the structural requirements for a cycloalkyl moiety in the potent hallucinogen 1-(1-phenylcyclohexyl)piperidine (PCP, 1), a series of structural analogues was synthesized in which the size of the cycloalkyl ring was varied from three carbons to eight carbons. Biological activities of these compounds were assessed in an in vitro assay (phencyclidine binding assay) and an in vivo assay (discriminative stimulus assay). As the cycloalkyl ring size decreased from that of cyclohexane (PCP), PCP-like activity declined in both assays, but as the cycloalkyl ring size became larger than cyclohexane, a sharp decline in PCP-like activity was observed in the in vivo assay, while activity in the in vitro assay was only slightly less than that of PCP. 1-(1-Phenylcyclooctyl)piperidine (8) had potent competitive binding properties in the in vitro binding assay but produced no observable PCP-like effects in the in vivo assay. The importance of the cycloalkyl ring in the structure of PCP was demonstrated by testing benzylpiperidine (2), which had almost no measurable activity in either assay.

Metabolism and excretion of normorphine in dogs.

Normorphine metabolism was studied in dogs given 20 mg of normorphine hydrochloride/kg sc. Free and (onjugated normorphine excreted in the urine over 144 hr represented 32 and 32%, respectively, of the administered dose. Eighty percent of the urinary excretion of the drug occurred within 9 hr. One percent of the administered dose was excreted as free normorphine in the feces. The urine was chromatographed on a column. Evaporation of the washing and methanolic effluent yielded a residue, which was purified by crystallization from aqueous methanol. Results of UV and IR studies, elemental analysis, and determination of normorphine and glucuronic acid content established the identity of this metabolite as normorphine 3-glucuronide. Dihydronormorphine and dehydronormorphine were detected with GLC-mass spectrometry as minor metabolites.

Biotransformation of morphine to dihydromorphinone and normorphine in the mouse, rat, rabbit, guinea pig, cat, dog, and monkey.

Biotransformation of morphine to dihydromorphinone and normorphine was studied in several mammalian species. Free and total dihydromophinone, morphine, and normorphine in the urine were determined, as propionyl derivatives, with a gas-chromatographic technique. Dihydromorphinone was detected as a morphine metabolite in the acid-hydrolyzed urine of all species studied except the dog and morphine-dependent man. Normorphine in both free and conjugated forms was detected in the urine of all species studied. The degree of biotransformation of morphine to dihydromorphinone in the guinea pig did not change during chronic administration of morphine sulfate, 25 mg/kg, daily for 28 days. The small amounts of dihydromorphinone and normorphine produced as metabolites make it unlikely that they play any significant role in the modification of the pharmacologic effects of morphine.

Identification of diacetylmorphine metabolites in humans.

With the techniques of column chromatography, TLC, and GLC, morphine, 6-acetylmorphine, normorphine, morphine 3-glucuronide, 6-acetylmorphine 3-glucuronide, and normorphine glucuronide were identified as metabolites of diacetylmorphine (heroin) in the urine of humans administered 10 mg iv/70 kg body weight.