Absorption kinetics of oral and rectal flecainide in healthy subjects

Summary The absorption kinetics of different pharmaceutical formulations of orally and rectally administered flecainide have been assessed in a cross-over study in 7 healthy volunteers. The subjects received single doses of flecainide after a washout period of at least one week. A tablet, an oral solution, a rectal solution and a 10 min i.v. infusion during 10 min each containing 100 mg flecainide were administered to the subjects in a randomized order.The mean absolute bioavailability was 98%, 78% and 81% for the rectal and oral solutions and the tablet. The lag time after administration of the oral solution was 0.33 h and it was 0.86 h after the tablet and 0.18 h after the rectal solution. The mean time to the peak serum concentration (t_max) after the rectal solution (0.67 h) was shorter than after either the tablet (4 h) or oral solution (1 h). The maximum serum concentration (C_max) was 0.29 mg · 1^–1 after the rectal solution, 0.14 mg · 1^–1 after the tablet and 0.17 mg · 1^–1 after the oral solution. All the volunteers showed significantly higher serum flecainide concentrations during the first 20 min of the absorption phase after rectal administration of 100 mg flecainide as a solution compared to its oral administration.In conclusion: based on the absolute bioavailability, C_max, t_max, and lag times, rectal administration of flecainide solution gave a better absorption profile than after oral tablet or solution.     

Enhanced Bioavailability of Cefoxitin Using Palmitoylcarnitine. II. Use of Directly Compressed Tablet Formulations in the Rat and Dog

The performance of tablets containing the absorption enhancer palmitoylcarnitine chloride (PCC) and the antibiotic cefoxitin (CEF) was determined by direct placement of tablets in the rat stomach, small intestine, and colon. While the bioavailability (F) of tablets containing 12 mg CEF without PCC ranged from 0.6 to 3.9%, the addition of 24 mg PCC resulted in an enhanced CEF bioavailability in the rat colon (mean ± SD: F = 57 ± 19%) and rat jejunum (F = 71 ± 16%) but not in the rat stomach. Following oral administration to dogs, tablets of 200 mg CEF without or with 600 mg PCC resulted in the same low bioavailabilities (7.0 ± 10.3 and 7.0 ± 3.6%, respectively). However, when these tablets were enteric coated, PCC improved CEF bioavailability from 2.44 ± 1.84 to 29.0 ± 13.4%. Therefore, the use of enteric-coated direct compressed tablets containing PCC and direct compression excipients improved the peroral bioavailability of a poorly absorbed compound.     

The Preparation and Evaluation of a Tablet Dosage Form of Cyclosporine in Dogs

Cyclosporine (CsA) is commercially available for oral administration as a solution in olive oil with alcohol and an emulsifier. To improve its variable absorption and low patient acceptability, several oral formulations were prepared and tested in vitro and in vivo in dogs. A tablet formulation prepared by direct compression was then selected for comparison with the commercial oil solution placed into soft gelatin capsules. The study involved a randomized crossover design in six dogs. In order to determine absolute bioavailability and to compensate for any time-dependent changes in clearance, an intravenous tracer dose of ³H-CsA was administered along with each oral test product on each of two occasions. Absolute bioavailability (mean ± SD) was 46.0 ± 11.1 and 45.4 ± 9.9% for the capsules and tablets, respectively. C _max, t _max, and mean absorption time were not significantly different between the two products. No differences were observed in the pharmacokinetics of the intravenously administered CsA in the two experiments, which were separated by 8–13 days. We conclude that the proposed tablet formulation for CsA is equivalent in dogs to the commercial dosage form placed into soft gelatin capsules.     

Influence of menthol on caffeine disposition and pharmacodynamics in healthy female volunteers

Objectives The present study was undertaken to determine whether a single oral dose of menthol affects the metabolism of caffeine, a cytochrome P₄₅₀ 1A2 (CYP1A2) substrate, and pharmacological responses to caffeine in people.Methods Eleven healthy female subjects participated in a randomized, double-blind, two-way crossover study, comparing the kinetics and effects of a single oral dose of caffeine (200 mg) in coffee taken together with a single oral dose of menthol (100 mg) or placebo capsules. Serum caffeine concentrations and cardiovascular and subjective parameters were measured throughout the study.Results Co-administration of menthol resulted in an increase of caffeine t_max values from 43.6±20.6 min (mean±SD) to 76.4±28.0 min (P<0.05). The C_max values of caffeine were lower in the menthol phase than in the placebo phase, but this effect was not statistically significant (P=0.06). (AUC)_0–24, (AUC)_0–, terminal half-life and oral clearance were not affected by menthol. Only nine subjects' cardiovascular data were included in the analysis because of technical problems during the measurements. After caffeine, heart rate decreased in both treatment phases. The maximum decrease in heart rate was less in the menthol phase (–8.9±3.9 beats/min) than in the placebo phase (–13.1±2.1 beats/min) (P=0.024). There were no statistically significant differences in systolic and diastolic blood pressures between the two treatments.Conclusions We conclude that a single oral dose of pure menthol (100 mg) delays caffeine absorption and blunts the heart-rate slowing effect of caffeine, but does not affect caffeine metabolism. The possibility that menthol slows the absorption of other drugs should be considered.     

Intra- and Inter-Subject Variabilities of CGP 33101 after Replicate Single Oral Doses of Two 200-mg Tablets and 400-mg Suspension

Purpose. The purpose of this study was to use a replicate designed trial to assess the overall, intra- and inter-subject variabilities in pharmacokinetic parameters of CGP 33101 after oral administration of tablets relative to that of powder suspended in water, and to determine the relative proportion of the intra-subject variance to the overall variability. Methods. Sixteen healthy subjects were randomly assigned to four groups to receive tablets and suspension twice in four different treatment sequences. The plasma concentration-time profile of CGP 33101 was characterized in terms of C_max, T_max, and AUC. Bioavailability of tablets relative to suspension and intra- and inter-subject variability were assessed by statistical analysis. Results and Conclusions. The overall variabilities in absorption kinetics of CGP 33101 in healthy subjects were small with CV's of the population mean values for AUC and C_max less than 26% for both tablets and suspension. Contribution of intra-subject variability to the overall variability was also small (~20%). Both the overall and intra-subject variabilities of AUC and C_max after suspension were larger than after the tablets. However, the differences in variability between tablets and suspension were not statistically significant (p > 0.05). The tablet formulation was bioequivalent to suspension in terms of rate and extent of absorption based on 90% conventional confidence intervals (for AUC and C_max) and Wilcoxon rank-sum test (for T_max).     

Flecainide acetate for the treatment of atrial and ventricular arrhythmias

Introduction: Flecainide is a class Ic antiarrhythmic agent available in Europe since 1982. The clinical development program of flecainide provided good data on its antiarrhythmic effect for the prevention of ventricular and supraventricular arrhythmias. The Cardiac Arrhythmia Suppression Trial (CAST), conducted to test whether the arrhythmia suppression translates into prevention of sudden death, assessed the impact of flecainide and encainide therapy in patients with frequent ventricular ectopics and reduced left ventricular function who had survived an infarction. In that population, flecainide and encainide increased mortality. Consequently, sodium channel blockers are now rarely used to prevent sudden death and are not recommended in patients with heart failure. Current European and North American guidelines recommend the use of flecainide in carefully selected patients with atrial fibrillation (AF) and no documented structural heart disease.

Areas covered: The aim of this review is to evaluate the available data on efficacy and safety of flecainide in all the spectrum of its indications including cardioversion of recent-onset AF, sinus rhythm maintenance in paroxysmal AF and management of ventricular tachyarrhythmias.

Expert opinion: In the setting of AF and in carefully selected patients without structural heart disease, flecainide has shown a good efficacy and safety for both cardioversion and sinus rhythm maintenance.     

Pharmacokinetic variability of flecainide in younger Japanese patients and mechanisms for renal excretion and intestinal absorption

The aims of the present study were to evaluate the variability of pharmacokinetics of flecainide in young Japanese patients and to investigate the mechanisms of renal excretion and intestinal absorption of the drug using cultured epithelial cells. First the plasma concentration data of flecainide was analysed in 16 Japanese patients aged between 0.07 and 18.30 years using a one‐compartment model. Considerable interindividual variability was observed in the oral clearance (CL/F) and the apparent volume of distribution (V/F) of flecainide in the young patients. Flecainide was transported selectively in the basolateral‐to‐apical direction in P‐glycoprotein‐expressing renal epithelial LLC‐GA5‐COL150 cell monolayers. The uptake of flecainide into intestinal epithelial LS180 cells was decreased significantly by acidification of the extracellular medium, and was inhibited by tertiary amines, such as diphenhydramine and quinidine. These findings in the present study suggest that flecainide is excreted by P‐glycoprotein in the renal tubule and is taken up by the postulated H⁺/tertiary amine antiporter in the intestine, and that functional variability of not only the hepatic drug‐metabolizing enzymes, but also the transporters in the kidney and intestine, may be responsible for the interindividual variability of systemic clearance (CL) and/or the bioavailability (F) of flecainide. Copyright © 2013 John Wiley & Sons, Ltd.     

Hypertrophic cardiomyopathy: A desensitized cardiac \-adrenergic system in the presence of normal plasma catecholamine concentrations

Only few data are available concerning the biochemical and functional state of the \-adrenergic system in hypertrophied human myocardium. The present study was to investigate the myocardial \-adrenergic signal transduction system in hypertrophic obstructive cardiomyopathy (HOCM).Thin myocardial strips were prepared from surgically excised, septal myocardium from 7 patients with HOCM and their force of contraction was measured in vitro. The positive inotropic effects of calcium and dihydro-ouabain, both acting independently of \-adrenoceptors and cAMP, were similar in these preparations to those, previously published, seen with nonfailing myocardium. In contrast, the \-adrenoceptor agonist isoprenaline and the phosphodiesterase inhibitor 3-isobutyl-l-methylxanthine (IBMX) had reduced positive inotropic effects. Their EC₅₀-values were about 10 fold higher than the respective EC₅₀-values published for nonfailing myocardium. The positive inotropic potencies of isoprenaline and IBMX were reduced in HOCM by as much as they were in the additionally investigated myocardium from 6 patients with severe mitral regurgitation (MR, NYHA III). In order to clarify whether the functional alterations are related to changes in the \-adrenoceptors, \-adrenoceptor density and \₁:\₂-adrenoceptor subtype distribution were determined in the same myocardium using ¹²⁵I-Iodocyanopindolol saturation binding.Myocardial \-adrenoceptor density was reduced to 68% in HOCM and to 56% in MR compared to nonfailing myocardium controls (NF: 64.8 ± 6.5 fmol/mg protein). In HOCM, this reduction was due to a selective down regulation of \₁-adrenoceptors (24.9 ± 3.7 fmol/mg protein vs NF: 46.4 ± 6.8 fmol/mg protein, P < 0.05), whereas \₂-adrenoceptor density was unchanged (19.0 ± 1.9 fmol/mg protein vs NF: 18.4 ± 3.3 fmol/mg protein, n.s.). In MR both \-adrenoceptor subtypes were reduced (\₁: 26.9 ± 1.4 fmol/mg protein, \₂: 9.6 ± 1.7 fmol/mg protein; both P < 0.05 vs NF). Electrochemically determined plasma catecholamine levels were elevated in MR. However, plasma catecholamine levels were normal or slightly below normal in HOCM.In summary, myocardial \-adrenoceptors are downregulated and their function is impaired in HOCM. This desensitization is not caused by a negative feedback regulation due to increased plasma catecholamines. The present results show that the desensitizations of the \-adrenergic system associated with HOCM has characteristics that indicate a major deviation in its development from that of the \-adrenergic desensitization previously described to occur in congestive heart failure.     

Rectal versus oral absorption of codeine phosphate in man

Rectal absorption of codeine phosphate from various dosage forms was studied in man. The rectal dosage forms included aqueous solutions and fatty suppositories. A comparison was made with an orally administered solution. The plasma concentrations of codeine were measured by means of HPLC analysis after a single dose of 60 mg codeine phosphate in a cross-over study in 7 volunteers. Compared with oral dosing rectal absorption from an aqueous solution or a fatty suppository produced an almost identical plasma concentration profile with similar interindividual variations. Comparing the absorption rate characteristics it appeared that rectal absorption from an alkaline solution containing codeine phosphate proceeded significantly (P < 0·05) more rapid than after oral dosing. No essential difference in bioavailability was observed between the various rectal and oral dosage forms.     

Sodium channel-blocking properties of flecainide,a class IC antiarrhythmic drug,in guinea-pig papillary muscles An open channel blocker or an inactivated channel blocker

Summary Effects of flecainide (a class IC antiarrhythmic drug) on the maximum rate of rise ( ) of action potentials (APs) were studied in guinea-pig papillary muscles, with special reference to their time, voltage, and action potential duration (APD) dependence in the presence and absence of nicorandil. Nicorandil was used to shorten APD, i.e., the time period of inactivation state of sodium channels. APs were recorded from the preparations using standard microelectrode techniques. Flecainide (5 mol/l) reduced without changing resting potential, AP amplitude, APD₅₀, and APD₉₀ examined at 1 Hz. The drug shifted the normalized -membrane potential curve (examined at 1/60 Hz) in the hyperpolarizing direction by 3.1 ± 0.8 mV (n = 6) (voltage dependence). The drug caused a frequency-dependent reduction of at 0.1 Hz, developed a use-dependent reduction of at 1 Hz with an onset time constant of 11.7 ± 0.4 s (n = 6), and slowed the recovery process of , whose resultant recovery time constant was 19.9 ± 1.2 s (n = 6) (time dependence). These flecainide-induced time-dependent reductions of were not antagonized by nicorandil (1 mmol/1) which shortened APD to about 1/4 of control (APD independence). These results suggest that flecainide is primarily an open channel blocker because its channel-blocking actions are independent of APD or the time period of inactivation.     

Characterization of the Oral Absorption of β-Lactam Antibiotics. I. Cephalosporins: Determination of Intrinsic Membrane Absorption Parameters in the Rat Intestine In Situ

The oral absorption of five cephalosporin antibiotics, cefaclor, cefadroxil, cefatrizine, cephalexin, and cephradine, has been studied using a single-pass intestinal perfusion technique in rats. Intrinsic membrane absorption parameters, unbiased by the presence of an aqueous permeability (diffusion or stagnant layer), have been calculated utilizing a boundary layer mathematical model. The resultant intrinsic membrane absorption parameters are consistent with a significant carrier-mediated, Michaelis-Menten-type kinetic mechanism and a small passive component in the jejunum. Cefaclor colon permeability is low and does not exhibit concentration dependent behavior. The measured carrier parameters (±SD) for the jejunal perfusions are as follows: cefaclor, J _max ^* = 21.3 (±4.0), K _m = 16.1 (±3.6), P _m ^* = 0, and P _c ^*= 1.32 (±0.07); cefadroxil, J _max ^* = 8.4 (±0.8), K _m = 5.9 (±0.8), P _m ^* = 0, and P _c ^* = 1.43 (±0.10); cephalexin, J _max ^* = 9.1 (±1.2), K _m = 7.2 (±1.2), P _m ^* = 0, and P _c ^* = 1.30 (±0.10); cefatrizine, J _max ^* = 0.73 (±0.19), K _m = 0.58 (±0.17), P _m ^* = 0.17 (±0.03), and P _c ^* = 1.25 (±0.10); and cephradine, J _max ^* = 1.57 (±0.84), K _m = 1.48 (±0.75), P _m ^* = 0.25 (±0.07), and P _c ^* = 1.06 (±0.08). The colon absorption parameter for cefaclor is P _m ^* = 0.36 (±0.06, where J _max ^* (mM) is the maximal flux, K _m (mM) is the Michaelis constant, P _m ^* is the passive membrane permeability, and P _c*is the carrier permeability. Aminocephalosporin perfusion results indicate that jejunal absorption in the rat occurs by a nonpassive process, with some of the compounds possessing a small but statistically significant passive component, while the colon permeability is low and follows a simple passive absorption mechanism.     

Evaluation of the absorption from 15 commercial theophylline products indicating deficiencies in currently applied bioavailability criteria

The biovailability of theophylline from alcoholic and aqueous oral solutions was compared to that from an intravenous dose in 12 normal adults. The alcoholic elixir surprisingly gave rise to a significantly greater (114 ±14%, mean±sd amount absorbed than did the intravenous dose. The aqueous solution (99±8%) and intravenous dose were statistically indistinguishable in this respect, and, furthermore, the extent of absorption from a 300-mg dose of the aqueous solution was 99±10% of that from a 500-mg dose, and not statistically different. The aqueous solution was thus employed in three subsequent studies as a standard with which to compare 13 different types of theophylline tablets, all marketed in the United States. Of the 13 tablets, eight showed bioavailability statistically distinguishable from that of the standard. Nevertheless, for only two tablets could it be claimed with 95% confidence that the bioavailability was less than 95%. For none can it be stated at this confidence level that the bioavailability is less than 90%. Bioavailability studies should include criteria of clinical significance in addition to criteria of statistical significance. Contrary to the usual rationale behind choice of a bioavailability standard, nine of the 12 uncoated tablets appeared to allow more rapid absorption of theophylline than did the standard oral solution, an aqueous syrup. Increasing the dose of syrup decreased the rate of theophylline absorption. Orally administered drug solutions may have properties more absorption rate limiting than the disintegration of many brands of tablet.This work was supported by FDA Contract No. 223-74-3145. Data management and analysis were achieved largely by the NIH-sponsored PROPHET system (ref.Proc. Natl. Comput. Conf. Exposition 43: 457, 1974). Dr. Guentert was supported by the Swiss National Science Foundation.     

Inhibition of IK,ACh current may contribute to clinical efficacy of class I and class III antiarrhythmic drugs in patients with atrial fibrillation

Inward rectifier potassium currents I_K1 and acetylcholine activated I_K,ACh are implicated in atrial fibrillation (AF) pathophysiology. In chronic AF (cAF), I_K,ACh develops a receptor-independent, constitutively active component that together with increased I_K1 is considered to support maintenance of AF. Here, we tested whether class I (propafenone, flecainide) and class III (dofetilide, AVE0118) antiarrhythmic drugs inhibit atrial I_K1 and I_K,ACh in patients with and without cAF. I_K1 and I_K,ACh were measured with voltage clamp technique in atrial myocytes from 58 sinus rhythm (SR) and 35 cAF patients. The M-receptor agonist carbachol (CCh; 2 μM) was employed to activate I_K,ACh. In SR, basal current was not affected by either drug indicating no effect of these compounds on I_K1. In contrast, all tested drugs inhibited CCh-activated I_K,ACh in a concentration-dependent manner. In cAF, basal current was confirmed to be larger than in SR (at −80 mV, −15.2 ± 1.2 pA/pF, n = 88/35 vs. −6.5 ± 0.4 pA/pF, n = 194/58 [myocytes/patients]; P < 0.05), whereas CCh-activated I_K,ACh was smaller (−4.1 ± 0.5 pA/pF vs. −9.5 ± 0.6 pA/pF; P < 0.05). In cAF, receptor-independent constitutive I_K,ACh contributes to increased basal current, which was reduced by flecainide and AVE0118 only. This may be due to inhibition of constitutively active I_K,ACh channels. In cAF, all tested drugs reduced CCh-activated I_K,ACh. We conclude that in cAF, flecainide and AVE0118 reduce receptor-independent, constitutively active I_K,ACh, suggesting that they may block I_K,ACh channels, whereas propafenone and dofetilide likely inhibit M-receptors. The efficacy of flecainide to terminate AF may in part result from blockade of I_K,ACh.     

Single-dose bioavailability of oral and intramuscular thiocolchicoside in healthy volunteers

A single dose of 8 mg of thiocolchicoside was administered to 12 healthy volunteers according to a Latin square design, either as tablets (reference), oral solution, or intramuscular injection. Serum thiocolchicoside concentrations showed an absorption phase followed by a biexponential decay with a terminal half-life (t_1/2β) of approximately 5 h, similar for the three formulations. The relative bioavailability of both oral formulations was approximately 25%, compared to the intramuscular formulation. There was a trend for the oral solution to have a slightly larger AUC and C_max, as well as a slightly shorter T_max, than the tablet formulation. However, the comparison of the two oral forms did not show statistically significant differences in the pharmacokinetic parameters C_max, T_max, and AUC, suggesting that the Coltramyl^® tablets have an adequate in vivo dissolution profile.     

Comparison of Zafirlukast (Accolate®) Absorption After Oral and Colonic Administration in Humans

Purpose. This study characterized the gastrointestinal (GI) absorptionof zafirlukast after oral and colonic administration in humans. Methods. Five healthy subjects received zafirlukast solution (40 mg)orally and via an oroenteric tube into the colon in a randomized,crossover fashion. Two additional subjects were dosed into the distalileum. Serial blood samples were obtained and plasma concentrationswere quantitated by HPLC. Results. Mean ± SD pharmacokinetic parameters after oral vs. colonicadministration were: AUC of 2076 ± 548 vs. 602 ± 373 ng*h/mL,respectively, and C_max of 697 ± 314 vs. 194 ± 316 ng/mL, respectively.Mean colon:oral AUC and C_max were 0.29 and 0.30, respectively.Median t_max values were 2.0 and 1.35 hr after oral and colonicadministration. First-order absorption rate constants (K_a and K_ac) wereestimated from a two-compartment model with first-order elimination.K_ac:K_a was <0.5 in 4 of the 5 subjects dosed in the colon. Conclusions. Zafirlukast was absorbed at multiple sites in the GI tract.The rate and extent of zafirlukast absorption was less after colonicthan oral administration. Zafirlukast was significantly absorbed in thedistal ileum. This study demonstrated that gamma scintigraphy, digitalradiography, and fluoroscopy can be used to track the movement andconfirm the location of the oroenteric tube in the GI tract.     

Pharmacokinetics of quinidine and three of its metabolites in man

Disposition parameters of quinidine and three of its metabolites, 3-hydroxy quinidine, quinidine N-oxide, and quinidine 10,11-dihydrodiol, were determined in five normal healthy volunteers after prolonged intravenous infusion and multiple oral doses. The plasma concentrations of individual metabolites after 7 hr of constant quinidine infusion at a plasma quinidine level of 2.9±(SD) 0.3 mg/L were: 3-hydroxy quinidine, 0.32±0.06 mg/L; quinidine N-oxide, 0.28±0.03 mg/L; and quinidine 10,11-dihydrodiol, 0.13±0.04 mg/L. Plasma trough levels after 12 oral doses of quinidine sulfate every 4 hr averaged: quinidine, 2.89±0.50 mg/L; 3-hydroxy quinidine, 0.83±0.36 mg/L; quinidine N-oxide, 0.40±0.13 mg/L; and quinidine 10,11-dihydrodiol, 0.38±0.08 mg/L. Relatively higher plasma concentrations of 3-hydroxy quinidine metabolite after oral dosing probably reflect first-pass formation of this quinidine metabolite. A two-compartment model for quinidine and a one-compartment model for each of the metabolites described the plasma concentration-time curves after both i.v. infusion and multiple oral doses. Mean (±SD) disposition parameters for quinidine from individual fits, after i.v. infusion were as follows: V ₁ ,0.37±0.09 L/kg; ₁,0.094±0.009 min ^–1; ₂, 0.0015±0.0002 min^–1; EX2, 0.013±0.002 min^–1;clearance (Cl_Q),3.86±0.83 ml/min/kg. Both plasma and urinary data were used to determine metabolic disposition parameters. Mean (±SD) values for the metabolites after i.v. quinidine infusion were as follows: 3-hydroxy quinidine: formation rate constant k_mf,0.0012±0.0005 min ^–1,volume of distribution, V_m,0.99±0.47 L/kg; and elimination rate constant, k_mu 0.0030±0.0002 min ^–1.Quinidine N-oxide: k_mf,0.00012±0.00003 min ^–1; V_m,0.068±0.020 L/kg; and k_mu,0.0063±0.0008 min ^–1.Quinidine 10,11-dihydrodiol: k_mf,0.0003±0.0001 min ^–1; V_m,0.43±0.29 L/kg; and k_mu,0.0059±0.0010 min ^–1.Oral absorption of quinidine was described by a zero order process with a bioavailability of 0.78. Concentration dependent renal elimination of 3-hydroxy quinidine was observed in two out of five subjects studied.This work was supported by funds from the grants GM 26691 and GM 28072 from the National Institute of General Medical Sciences, NIH. A. Rakhit was the recipient of a Training Grant Traineeship from NIH. T. W. Guentert is grateful for support from the Swiss National Science Foundation.Professor Sidney Riegelman. deceased April 4, 1981.     

Absolute Bioavailability and Absorption Profile of Cyanamide in Man

A pharmacokinetic study of cyanamide, an inhibitor of aldehyde dehydrogenase (EC1.2.1.3) used as an adjuvant in the aversive therapy of chronic alcoholism, has been carried out in healthy male volunteers following intravenous and oral administration. Cyanamide plasma levels were determined by a sensitive HPLC assay, specific for cyanamide. After intravenous administration cyanamide displayed a disposition profile according to a two-compartmental open model. Elimination half-life and total plasma clearance values ranged from 42.2 to 61.3 min and from 0.0123 to 0.0190 L · kg ^–1 · min^–1, respectively. After oral administration of 0.3, 1.0, and 1.5 mg/kg ± SEM values of C_max, t_max (median) and AUC were 0.18 ± 0.03, 0.91 ± 0.11, and 1.65 ± 0.27 g · ml ^–1 ; 13.5, 13.5, and 12 min; and 8.59 ± 1.32, 45.39 ± 1.62, and 77.86 ± 17.49 g · ml ^–1 · min, respectively. Absorption was not complete and the oral bioavailability, 45.55 ± 9.22, 70.12 ± 4.73, and 80.78 ± 8.19% for the 0.3, 1.0, and 1.5 mg/kg doses, respectively, increased with the dose administered. The models that consider a first-order absorption process alone (whether with a fixed or variable bioavailability value as a function of dose) or with loss of drug due to presystemic metabolism (with zero-order or Michaelis–Menten kinetics) were simultaneously fitted to plasma level data obtained following 1 mg/kg iv and 0.3, 1.0, and 1.5 mg/kg oral administrations. The model that best fit the data was that with a first-order absorption process plus a loss by presystemic metabolism with Michaelis–Menten kinetics, suggesting the presence of a saturable first-pass effect.     

Pharmacokinetics of N-desmethyldiazepam in healthy volunteers after single daily doses of dipotassium chlorazepate

Dipotassium chlorazepate was administered to 12 healthy volunteers (8 males and 4 females), aged 22–38 years, as a single daily dose of 20 mg for 14 days. Plasma concentrations of N-desmethyldiazepam were monitored with a gas-chromatographic method during the medication period and for 5 days after withdrawal of the drug. The plasma half-life (t _1/2), the elimination coefficient (K ), the concentration ( ), and the apparent volume of distribution (V ) were calculated at steady state, and the mean values±SEM were 53±6 h, 0.0147±0.0013 h^-1, 884±73 ng/ml, and 1.13±0.08 l/kg, respectively. A moderate interindividual variability was observed regarding these parametes. There was no tendency toward a biexponential elimination. A significant difference in the apparent volume of distribution was found when males and females were compared.     

Oral Absorption of Peptides: The Effect of Absorption Site and Enzyme Inhibition on the Systemic Availability of Metkephamid

In this study the intestinal degradation and absorption of a synthetic pentapeptide, metkephamid, were investigated in the rat by determination of its wall permeabilities in the small and large intestine and the extent and mechanism of its intestinal degradation. The peptide was metabolized in the gut wall through contact with membrane-bound enzymes in the brush border membrane. The extent of metabolic inactivation depended on the intestinal segment investigated and decreased in the axial direction. No metabolism was found in the colon. The dimensionless wall permeabilities (P _w*), determined by single-pass perfusion, were also site dependent. P _w* was highest in the ileum [1.91 ± 0.24, (SE); n = 4], followed by the jejunum (1.64 ± 0.34; n = 4) and the colon (0.67 ± 0.38; n = 4). Based on the permeability data alone and under the assumption of no presystemic metabolism, complete bioavailability would be predicted for metkephamid. However, following oral administration, the mean absolute bioavailability was only 0.22 ± 0.065% (n = 3), indicating the overall dominance of degradation in the absorption process. Thus future strategies in oral peptide delivery should focus on increasing the stability of the peptide in the intestine by modifying the peptide structure and/or delivering the compound to an intestinal segment showing little or no enzymatic degradation.     

Pharmacokinetics of a Single Intravenous and Oral Dose of Pafenolol—a Beta1Adrenoceptor Antagonist with Atypical Absorption and Disposition Properties—in Man

The pharmacokinetics of pafenolol were studied in eight young healthy individuals. The doses were 10 mg iv and 40 mg orally. Each dose was labeled with 100 µCi [³H]pafenolol. The plasma concentration–time curve of the oral dose exhibited dual maxima. The second peak was about four times higher than the first one. Maximum concentrations were attained after 0.9 ± 0.2 and 3.7 ± 0.6 hr. The mean bioavailability (F) of the oral dose was 27.5 ± 15.5%. The reduction in F was due mainly to incomplete gastrointestinal absorption. The drug was rapidly distributed to extravascular sites; t _1/2l was 6.6 ± 1.8 min. The volumes of distribution were V _c = 0.22 ± 0.08 liter/kg, V _ss = 0.94 ± 0.17 liter/kg, and V _z = 1.1 ± 0.16 liters/kg. The iv dose of pafenolol was excreted in unchanged form in the urine to 55.6 ± 5.1% of the given dose and in the feces to 23.8 ± 5.7% within 72 hr. The corresponding recoveries of the oral dose were 15.8 ± 5.9 and 67.0 ± 10.2%, respectively. About 10% of both doses was recovered as metabolites in the excreta. Approximately 6% of the oral dose was metabolized to nonabsorbable compounds in the intestine. The mean total plasma clearance was 294 ± 57 ml/min, of which renal clearance, metabolic clearance, and gastrointestinal and/or biliary clearance were responsible for 165 ± 31, 31 ± 15, and 95 ± 32 ml/min, respectively. The half-life of the terminal phase determined from plasma levels up to 24 hr after dosing was 3.1 ± 0.3 hr for the iv dose and 6.7 ± 0.7 hr for the oral dose.