The pharmacokinetics of aspirin in rats and the effect of buffer

Aspirin (acetylsalicyclic add) was administered to rats intravenously, orally, and intraintestinally at different doses or in different dosage forms. The distribution and elimination kinetics of aspirin in rats following intravenous administration were best described by a two-compartmental open system and were dose independent up to 15 mg/kg. The terminal elimination half-life following intravenous dosing (10 mg/kg) was 3.36±0.85min (n=15) with the clearance being 8.40±1.24 L/(kg.hr). Intravenous distribution and elimination kinetics of aspirin in rats were not influenced by an orally administered buffered solution with a buffer capacity of 0.933 mEq ANC (acid neutralizing capacity) per kg of body weight. However, this orally buffered solution did change the gastrointestinal absorption kinetics of aspirin in rats. The absolute bioavailable dose of aspirin was 56.6±10.4% (n=6)following its administration in an unbuffered solution while it was only 31.8±8.0% (n=6)following administration in the buffered solution. The corresponding values of the absolute bioavailable doses were 43.4±3.7% and 25.5±1.8% following intraintestinal administration. The lower systemic availability of aspirin in the presence of buffer is attributed to a greater fraction of the administered dose becoming available for absorption from the intestine where the extraction efficiency is higher than that in the stomach.     

Apparent dose-dependent absorption of chlorothiazide in dogs

The purpose of this study was to determine the effect of oral dose on the absorption of chlorothiazide in the dog. Chlorothiazide was quantitatively excreted in the urine after administration of 50-mg and 250-mg intravenous doses. In contrast, the urinary recovery of chlorothiazide after oral administration showed appreciable interanimal variation and decreased from 70.4% to 26.7% on the average as the oral dose was increased from 125 mg to 750 mg. Oral administration of a single 15-mg dose of propantheline bromide (a potent inhibitor of gastric emptying and intestinal motility) at –1 hr increased the absorption of a 250 mg oral dose of chlorothiazide in three out of four dogs. These results suggest that chlorothiazide absorption is dose dependent and apparently site specific.This research was supported in part by Grants GM 20852 and GRS-RR0545415 from the National Institutes of Health, Bethesda, Md.This article was presented in part before the Basic Pharmaceutics Section Meeting, APhA Academy of Pharmaceutical Sciences, Hollywood, Florida, November 1978.     

Absolute bioavailability, rate of absorption, and dose proportionality of sulpiride in humans.

The pharmacokinetics of orally administered sulpiride was determined in a series of three studies. In the first study, 12 subjects received an oral solution (200 mg) and an iv dose (100 mg). The second study also included an iv dose, and examined the absorption of 200-, 300-, and 400-mg doses given as 50-mg capsules to six subjects. The third study compared the bioavailability of a 200-mg capsule dose with a 200-mg im dose in eight subjects. The concentration of sulpiride in plasma, red blood cells, and urine was measured by HPLC. The disposition of the drug was generally best described by a two-compartment pharmacokinetic model, with absorption appearing to occur by two sequential zero-order processes. The fraction of dose absorbed after oral administration was approximately 30% based on plasma and urine data. After the 200-mg dose, the mean elimination half-life was 7.0 h, and the mean residence time was 8.4 h. For each subject, total clearance, corrected for the fraction absorbed, and renal clearance were similar. The dose proportionality study demonstrated linear disposition kinetics.     

Minimal biliary excretion and enterohepatic recirculation of metoclopramide in patients with extrahepatic cholestasis

Summary The biliary excretion and apparent oral clearance of metoclopramide (MCL) were determined after oral administration of 1 mg MCL/kg body weight to 10 patients suffering from extrahepatic cholestasis with nasobiliary tube for drainage of the common bile duct. A bilioduodenal endoprosthesis was subsequently fitted in 6 of these patients, i.e. the enterohepatic circulation was restored, and the apparent oral clearance was re-determined.Biliary excretion, comprising free MCL and the products of conjugation, accounted for less than 1% of the administered dose. In accordance with this, the median areas under the plasma concentration-time-curves AUC(0–15 h) in patients with intact and interrupted enterohepatic recirculation were of similar size. The pharmacokinetic values in patients with cholestasis (median apparent oral clearance 0.5 l·kg^–1·h^–1; median t_1/2 4.5 h) were similar to those previously reported in patients with healthy liver function.We conclude that it is not necessary to adjust single doses of MCL in patients recovering from obstructive jaundice.     

Suramin as a Chemosensitizer: Oral Pharmacokinetics in Rats

Purpose. The purpose of this study was to determine if the 10-50 M plasma concentrations of suramin required to produce chemosensitization could be achieved by oral administration. Methods. Rats were given an oral dose of 100, 300, or 500 mg/kg unlabeled suramin by oral gavage. Rats receiving the 300 mg/kg oral dose of suramin also received a concomitant intravenous bolus injection of 50 Ci/kg of [³H]suramin, administered 57 min after the oral dose. The intravenous data were used to calculate the clearance. Serial plasma samples were collected over 24-336 h. Plasma concentration-time profiles were analyzed using noncompartmental and compartmental methods. The pharmacokinetic parameters derived for the 300 mg/kg oral and 50 Ci/kg intravenous doses were used to calculate the bioavailability and AUC at the three oral dose levels. Results. Plasma concentrations declined biexponentially following intravenous administration, with a distribution half-life of 2 h and an estimated terminal half-life of 276 h. Suramin absorption following oral gavage was variable and incomplete with mean maximal plasma concentrations of 9.04, 72.6, and 64.4 g/ml at doses of 100, 300, and 500 mg/kg, respectively. Seven of 15 rats exhibited two peak plasma concentrations at 1 h and 3 to 12 h, suggesting the existence of multiple absorption sites and/or enterohepatic circulation. Oral bioavailability, calculated using the clearance of the intravenous tracer dose, was <3% at all three dose levels. Conclusions. While plasma concentrations resulting from the 300 and 500 mg/kg oral doses of suramin were in the concentration range required to produce chemosensitization, the low bioavailability limits the usefulness of oral administration.     

Pharmacokinetics of low-dose oral modified release,soluble and intravenous aspirin in man,and effects on platelet function

Summary The pharmacokinetics of low-dose aspirin and the resulting salicylic acid were studied in 6 healthy volunteers. Each received a single 50-mg dose of (1) oral modified release capsules, (2) oral solution and (3) intravenous solution. The volunteers also received 50 mg modified release capsules daily for 6 days to determine the effect on collagen, ADP and arachidonate induced platelet aggregation and thromboxane production, and to compare the pharmacokinetics after repeated dosing with the parameters obtained after the single dose.The formulation and route of administration profoundly influenced several pharmacokinetic parameters for aspirin: the maximum concentration (C_max, ng·ml^–1) was 221 and 191 after modified release for single and chronic dosing respectively, 1323 after the oral solution and 6000 after intravenous injection; the time to achieve this maximum concentration (t_max, h) was 3.42 and 3.02 after modified release for single and chronic dosing respectively, and 0.29 after the oral solution; the area under the plasma drug concentration versus time curve (AUC, µg·h·ml^–1) was 0.38 and 0.27 after modified release single and chronic dosing respectively, 0.68 after the oral solution and 1.57 after intravenous injection.The elimination of aspirin after the two solutions was at least biphasic. The terminal phase rate constant ranged from 1.52 h^–1 after intravenous injection to 1.88 h^–1 after the oral modified release form. The absorption of the oral forms of aspirin was complete as reflected by the total recovery of the doses as salicylic acid in urine. The pharmacokinetic parameters for salicylic acid showed similar t_max and C_max for the oral solution and intravenous injection but, as for aspirin, C_max was least and t_max greatest when the modified release form was used.After 7 days of modified release aspirin platelet aggregation and thromboxane formation in response to collagen and arachidonate were markedly inhibited. There was no inhibition of ADP-induced aggregation, but thromboxane production in response to ADP was abolished.     

Kinetics of indomethacin absorption,elimination, and enterohepatic circulation in man

There are no discernible quantitative differences in the biotransformation and the excretion of indomethacin following oral, rectal, and intravenous administration of indomethacin-¹⁴ C. Approximately 50% (range 24–115% for n=6) of an intravenous dose undergoes enterohepatic circulation. Thus the bioavailability of indomethacin to the systemic circulation may exceed the administered dose. Relative to the intravenous dose, indomethacin is 80 and 100% bioavailable from suppositories and capsules, respectively. Absorption and/or reabsorption appears to be more rapid and uniform by the rectal route. Recognition of the attributes of biliary recycling also helps to explain the observed variability in apparent plasma half-life, while their neglect requires alternative explanations for anomalies between the disappearance rate from plasma and the corresponding appearance rate in urine.     

Effect of a single cyclosporine dose on the single-dose pharmacokinetics of sitagliptin (MK-0431), a dipeptidyl peptidase-4 inhibitor, in healthy male subjects

Sitagliptin (MK-0431) is an orally active, potent, and selective dipeptidyl peptidase-4 inhibitor used for the treatment of patients with type 2 diabetes mellitus. Sitagliptin has been shown to be a substrate for P-glycoprotein in preclinical studies. Cyclosporine was used as a probe P-glycoprotein inhibitor at a high dose to evaluate the potential effect of potent P-glycoprotein inhibition on single-dose sitagliptin pharmacokinetics in healthy male subjects. Eight healthy young men received a single oral 600-mg dose of cyclosporine with a single 100-mg oral sitagliptin dose and a single oral 100-mg sitagliptin dose alone in an open-label, randomized, 2-period, crossover study. Single doses of sitagliptin with or without single doses of cyclosporine were generally well tolerated. The sitagliptin AUC(0-infinity) geometric mean ratio was 1.29 with a 90% confidence interval of (1.24, 1.34). The sitagliptin Cmax geometric mean ratio was 1.68 with a 90% confidence interval of (1.35, 2.08). Cyclosporine coadministration did not appear to affect apparent sitagliptin renal clearance, t(1/2), or C(24 h), suggesting that effects of these high doses of cyclosporine are more likely due to enhanced absorption of sitagliptin, potentially through inhibition of intestinal P-glycoprotein. These results rationalize the use of a single high-dose cyclosporine as a probe inhibitor of P-glycoprotein for compound candidates whose elimination is less dependent on CYP3A4-mediated metabolism.     

Physiologically based pharmacokinetic modeling of cyclotrimethylenetrinitramine in male rats

A physiologically based pharmacokinetic (PBPK) model for simulating the kinetics of cyclotrimethylene trinitramine (RDX) in male rats was developed. The model consisted of five compartments interconnected by systemic circulation. The tissue uptake of RDX was described as a perfusion‐limited process whereas hepatic clearance and gastrointestinal absorption were described as first‐order processes. The physiological parameters for the rat were obtained from the literature whereas the tissue : blood partition coefficients were estimated on the basis of the tissue and blood composition as well as the lipophilicity characteristics of RDX (logP = 0.87). The tissue : blood partition coefficients (brain, 1.4; muscle, 1; fat, 7.55; liver, 1.2) obtained with this algorithmic approach were used without any adjustment, since a focused in vitro study indicated that the relative concentration of RDX in whole blood and plasma is about 1 : 1. An initial estimate of metabolic clearance of RDX (2.2 h^?1 kg^?1) was obtained by fitting PBPK model simulations to the data on plasma kinetics in rats administered 5.5 mg kg^?1 i.v. The rat PBPK model without any further change in parameter values adequately simulated the blood kinetic data for RDX at much lower doses (0.77 and 1.04 mg ^?1 i.v.), collected in this study. The same model, with the incorporation of a first order oral absorption rate constant (K_a 0.75 h^?1), reproduced the blood kinetics of RDX in rats receiving a single gavage dose of 1.53 or 2.02 mg kg^?1. Additionally, the model simulated the plasma and blood kinetics of orally administered RDX at a higher dose (100 mg kg^?1) or lower doses (0.2 or 1.24 mg kg^?1) in male rats. Overall, the rat PBPK model for RDX with its parameters adequately simulates the blood and plasma kinetic data, obtained following i.v. doses ranging from 0.77 to 5.5 mg kg^?1 as well as oral doses ranging from 0.2 to 100 mg kg^?1. Published in 2009 by John Wiley & Sons, Ltd.     

Pharmacokinetic study of doxycycline polyphosphate+ after simultaneous ingestion of milk

Pharmacokinetic parameters of doxycycline polyphosphate were studied in healthy volunteers after oral administration of a single 200 mg dose of this antibiotic with a breakfast containing or not 200 ml of whole milk. Ingestion of milk had only mild effect upon absorption parameters of doxycycline; only a moderate increase of the lag-time was significant. Elimination parameters of doxycycline were impaired by milk; a decrease of the terminal half-life from 28 h to 15 h, and apparent decrease of the enterohepatic circulation and an increase in total body clearance from 40 to 62 ml/min. were observed.     

Apparent dose-dependent absorption of chlorothiazide in dogs.

The purpose of this study was to determine the effect of oral dose on the absorption of chlorothiazide in the dog. Chlorothiazide was quantitatively excreted in the urine after administration of 50-mg and 250-mg intravenous doses. In contrast, the urinary recovery of chlorothiazide after oral administration showed appreciable interanimal variation and decreased from 70.4% to 26.7% on the average as the oral dose was increased from 125 mg to 750 mg. Oral administration of a single 15-mg dose of propantheline bromide (a potent inhibitor of gastric emptying and intestinal motility) at--1 hr increased the absorption of a 250 mg oral dose of chlorothiazide in three out of four dogs. These results suggest that chlorothiazide absorption is dose dependent and apparently site specific.     

Cutaneous Absorption of Indomethacin From Two Topical Preparations in Volunteers

The percutaneous absorption of indomethacin in 0.5 % or 1 % solution or 1 % gel at a dose of 50 mg or 100 mg indomethacin was compared in a randomized complete block design in seven healthy volunteers. The formulations were applied over an area of 12 dm² under an 8 h occlusion dressing. In addition, in the same volunteers the plasma concentration curves were determined after a single oral dose of 50 mg indomethacin. Indomethacin and some of its metabolites were determined with modified, existing assays using HPLC-fluorescence or gas chromatography-mass spectrometry. On the basis of a newly developed method, it was possible to separate and quantify O-desmethylindomethacin and N-deschlorobenzoyl-O-desmethylin-domethacin. After cutaneous administration of the two drug formulations, peak indomethacin plasma concentration of 95 ng/ml and 130 ng/ml were found between 4 and 8 h; the cutaneous bioavailability was approximately 20 % of the oral dose, as judged by comparing the areas under the plasma concentration time curves (AUC) and the amount of metabolites excreted into the urine. Percutaneous absorption did not change the metabolic pattern in the urine that is obtained after oral administration.     

Pharmacokinetics of fluvastatin after single and multiple doses in normal volunteers.

The pharmacokinetics of fluvastatin, a potent inhibitor of hydroxymethylglutaryl-CoA reductase and thus cholesterol synthesis, have been studied in 24 normal male volunteers who received [3H] fluvastatin in three different studies: a single-dose study using oral doses of 2 or 10 mg, an absolute bioavailability study using doses of 2 mg intravenously or 10 mg orally, and a multiple-dose study using 40 mg orally once daily for 6 days. Serial blood and plasma samples and complete urine and feces were collected and analyzed for total radioactivity as well as for intact fluvastatin. Fluvastatin was rapidly and almost completely (greater than 90%) absorbed from the gastrointestinal tract, although the estimated bioavailability from the 2- and 10-mg doses was only 19 to 29% because of extensive first-pass metabolism. Fluvastatin pharmacokinetics appeared to be linear over the 2- to 10-mg dose range, as indicated by dose-proportional blood levels of total radioactivity and the parent drug. Absorbed fluvastatin was completely metabolized before excretion, the biliary/fecal route being the major excretory pathway. The recovery of radioactivity after a single dose was virtually complete within 120 hours. The terminal half-lives of fluvastatin and total radioactivity averaged 0.5 to 1 hour and 55 to 71 hours, respectively, whereas the total body clearance of fluvastatin was 0.97 L/hour/kg. Repeated oral administration of 40-mg doses of [3H]fluvastatin resulted in no time-related change in pharmacokinetic characteristics, but this dose yielded greater than proportional increases in circulating levels of the parent drug, thus suggesting a saturable first-pass effect on fluvastatin.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of aspirin and indomethacin on the serum and urinary calcium, magnesium and phosphate

Recent data have shown that administration of prostaglandin inhibitors to patients with hypercalciuric nephrolithiasis decreased urinary calcium excretion, implying a possible role for prostaglandins in calcium excretion. To explore this hypothesis, we investigated the effect of single dose or 7 days' administrations of aspirin (100 mg/kg orally) or indomethacin (20 mg/kg, orally) on the urinary and serum concentrations of calcium, magnesium and inorganic phosphate. Experiments were performed in normocalcaemic and hypercalcaemic rats. Hypercalcaemia and hypercalciuria were induced in male Wistar albino rats by administration of vitamin D3 (20,000 IU/daily) for 7 days. Aspirin and indomethacin both significantly lowered the urinary calcium excretion in normocalciuric and hypercalciuric rats. The acute administration of indomethacin caused greater reduction of calcium excretion than that produced by the acute administration of aspirin, whereas aspirin showed greater activity than indomethacin after the long-term use of each. Aspirin induced hypocalcaemia in normocalcaemic rats and abolished the hypercalcaemia in hypercalcaemic rats. On the contrary, indomethacin, a specific prostaglandin biosynthesis inhibitor, increased serum levels of calcium. Hypophosphataemia was observed only after the administration of a single dose of aspirin in normocalcaemic rats, while the reduction of urinary phosphate excretion was investigated in hypercalciuric rats after the acute and chronic administration of indomethacin. Serum levels of phosphate were not altered significantly by acute or chronic administration of indomethacin. A single dose of indomethacin significantly reduced urinary excretion of magnesium in both groups of rats. However, the acute and chronic administration of aspirin resulted in non-significant changes in serum and urinary concentrations of magnesium. These data suggest that aspirin has hypocalcaemic and hypocalciuric actions while indomethacin has only a hypocalciuric effect. Aspirin may produce these actions by two mechanisms, one of them like that of indomethacin which is dependent on the inhibition of biosynthesis of prostaglandins, and another possible mechanism that is not related to the inhibition of prostaglandin biosynthesis. This suggestion may be supported by the discrepancy between the effects of aspirin and indomethacin on the renal handling and serum concentrations of magnesium and inorganic phosphate.     

Pharmacokinetics of pentachlorophenol in man

Pentachlorophenol (PCP) was given orally to three volunteers at single doses of 3.9, 4.5, 9, and 18.8 mg. Daily urinary excretion of PCP and PCP conjugated to glucuronic acid was monitored using gas chromatography with electron capture detection (GC/ECD). Based on first-order elimination kinetics an elimination half-life of 20 days was derived.To eliminate interference by the uncontrolled absorption of PCP from the environment 0.98 mg ¹³C-PCP was taken by one of the volunteers. PCP levels in urine and plasma were determined using mass spectrometry (GC/ MS) with negative chemical ionization. An elimination half-life of 17 days was found in both urine and blood. The collected data were used to calculate the clearance of PCP: a value of 0.07 ml/min was found. The long elimination half-life of PCP is explained by the low urinary clearance due to the high plasma protein binding (>96%) and the tubular reabsorption. The pH-dependency of the elimination of PCP was investigated, and a distinct increase in the daily excretion was observed following alkalinization by oral administration of sodium bicarbonate.In order to elucidate the role of the enterohepatic circulation as a possible pool for PCP in humans, the bile of cholelithiasis patients with postoperative T-drainage was investigated for PCP and compared with the corresponding urine and plasma levels, but no accumulation of PCP in the enterohepatic circulation could be observed.The daily elimination and plasma levels of PCP in a group of individuals without a specific exposition were found to range from 10 to 48 g/day and 19 to 36 g/l, respectively.     

Natriuretic and diuretic effects of cicletanine in conscious,hydrated, normotensive rats

The natriuretic and diuretic actions of cicletanine, a novel agent with vasorelaxant and antihypertensive properties, were examined in conscious, hydrated, normotensive rats. Cicletanine, the (+)- and (?)-enantiomers of cicletanine, hydrochlorothiazide (HCTZ), or vehicle(s) were administered orally or intravenously (1, 3, 10, 30 mg base/kg) to water-loaded (27 ml/kg) rats and 3 hr urine volume, Na⁺ and K⁺ were measured. Racemic cicletanine (3 mg/Kg, p.o.) caused a significant increase in urinary Na⁺(+174%) and K⁺ (+46%) excretion, unaccompanied by diuresis. Diuresis was detected only with larger oral doses of racemic cicletanine (10–30 mg/kg). Oral administration of a 1-mg/kg dose of (+)-cicletanine caused significant natriuresis that was not detected with either racemic or (?)-cicletanine. The (+)-enantiomer (3–30 mg/kg) produced natriuresis and diuresis quantitatively similar to that of racemic cicletanine. By contrast, (?)-cicletanine induced only slight natriuresis, kaliuresis, and diuresis upon administration of the largest dose (30 mg/kg, p.o.). Intravenous administration of the racemate and enantiomers of cicletanine caused natriuretic/diuretic activity that was very similar to that seen with oral administration. The natriuresis caused by a 3-mg/kg dose of racemic cicletanine was unaffected by indomethacin. However, indomethacin attenuated the natriuresis and eliminated the diuresis produced by the 10- and 30-mg/kg doses of cicletanine. Indomethacin had no effect on the kaliuretic actions of cicletanine. Indomethacin blunted the natriuresis and eliminated the diuresis caused by all doses of HCTZ. In conclusion, the natriuretic, kaliuretic, and diuretic effects of racemic cicletanine in the conscious, hydrated, normotensive rat appear to be mediated primarily by the ( + )-enantiomer. A dose-dependent separation exists between the natriuretic and diuretic actions of cicletanine, with only natriuresis noted at smaller doses. The natriuresis caused by racemic cicletanine has both indomethacin-resistant and indomethacin-sensitive components, while cicletanine-induced diuresis appears to be mediated exclusively by prostaglandins.     

Pharmacokinetic and Metabolic Disposition of p-Chloro-m-xylenol (PCMX) in Dogs

The pharmacokinetic and metabolic profile of p-chloro-m-xylenol (PCMX) was studied in healthy mongrel dogs after intravenous and oral administration of single doses of 200 and 2000 mg of PCMX, respectively. Calculation of pharmacokinetic parameters was based on compartmental and noncompartmental methods. The mean pharmacokinetic parameters of elimination half-life and mean residence time were 1.84 and 1.69 hr, respectively. The apparent volume of distribution at steady state was estimated to be 22.4 liters, and the plasma clearance was 14.6 liters/hr. The bioavailability of PCMX was 21%, indicating low absorption for this drug. PCMX's metabolite data show that a presystemic elimination process (first-pass effect) is also occurring. PCMX plasma concentrations after intravenous administration of 500-, 200-, and 100-mg doses were found to be proportional to the dose given, demonstrating that the pharmacokinetic profile of PCMX is linear over the dose range studied. Biotransformation studies showed that urinary excretion was not the major route for rapid elimination of unchanged PCMX and almost all material excreted in urine was associated with the conjugated species (glucuronides and sulfates). Statistical significant differences were not found (P > 0.05) between the percentages excreted in urine of PCMX and its conjugated metabolites after intravenous and oral administration. The percentages excreted in urine after iv and oral doses of unchanged PCMX were, respectively, 0.45 and 0.37; total conjugates, 46.3 and 43.3; sulfates, 38.1 and 33.2; and glucuronides, 8.2 and 10.2.     

Evidence for dissolution rate-limited absorption of COL-3, a matrix metalloproteinase inhibitor,leading to the irregular absorption profile in rats after oral administration

Purpose. This study was undertaken to elucidate the underlying mechanism of the irregular absorption profiles of COL-3, a matrix metalloproteinase inhibitor, with a double- or plateau-peak concentration after a single oral dose administration of COL-3 suspension to rats. Methods. The gastrointestinal absorption profiles of COL-3 in rats were assessed by comparing serum drug concentration curves after the following various modes of drug administration: oral and intraduodenal doses, oral doses of COL-3 in fine and coarse suspensions, intraduodenal dosing to the bile-duct intact and cannulated (BDC) rats, and oral doses with and without food. In addition, the biliary excretion of COL-3 in the BDC rats was examined. Results. Neither variable gastric emptying nor enterohepatic recycling was the source of the irregular gastrointestinal absorption of COL-3 in rats. Reduction in particle size, presence of food and endogenous bile emerged as the determinants of the oral absorption of COL-3 by enhancing the dissolution of the solid drug in the gastrointestinal fluids. Flip-flop of the absorption and elimination rate constants was noted only for COL-3 after intraduodenal administration of the coarse suspension to the BDC rats with the bile flow diverged out of the body. Conclusions. Variability in dissolution rate-limited absorption was the main cause of the irregular absorption of COL-3 after oral administration of its solid dosage form.     

Pharmacokinetics of cibenzoline after single and repetitive dosing in healthy volunteers

Twenty-five healthy, adult male volunteers entered two open-label parallel studies, each designed to define the pharmacokinetics of single and multiple oral doses of cibenzoline. Each volunteer received a single 160-mg oral dose of cibenzoline followed two or three days later by 160 mg of cibenzoline q12h for seven days. Plasma concentration-time profiles and urinary excretion rate data were used to determine pharmacokinetic parameters for unchanged drug. The apparent half-life following administration of the last dose (9.7 hours) was slightly longer than that observed after the first dose (8.4 hours). Total body clearance and nonrenal clearance were decreased after the last dose compared with the first dose, whereas renal clearance was not significantly altered. After both the first and last dose, the renal clearance greatly exceeded the glomerular filtration rate, suggesting that tubular secretion participates in the renal excretion of cibenzoline. Plasma concentrations from samples collected during the multiple-dose regimen suggest that a slight but statistically significant diurnal variation in the absorption and/or clearance of drug occurred during the course of the study. Overall, the pharmacokinetics of cibenzoline are characterized by a slightly longer half-life during multiple dosing than that observed following a single dose, due to a decrease in the nonrenal clearance. The multiple-dose pharmacokinetics reported herein are consistent with bid dosing for the maintenance of therapeutic plasma concentrations in patients taking chronic therapy.     

Kinetics of cotinine after oral and intravenous administration to man

Summary Cotinine, the main metabolite of nicotine, was administered intravenously to healthy male non-smoking volunteers in doses of 5, 10 and 20 mg, and orally in doses of 10 and 20 mg.Intravenous administration was characterized by a dose-independent half-life of 12.2 h, mean residence time of 15.9 h, total clearance of 3.64 l h^–1 and a volume of distribution of 56.5 l. Renal clearance was 0.46 l h^–1 and approximately 12.0% of the dose was excreted unchanged in the urine. The mean absorption time after oral dosing ranged between 1 and 3 h, the peak concentration was reached within 45 min and the mean elimination half-lives were 12.9 and 11.7 h, respectively, after the 10 and 20 mg doses. Systemic bioavailability ranged between 0.84 and 1.11 following 10 mg and between 0.97 and 1.03 following the 20 mg dose. Mean urinary recovery and renal clearance were almost identical with the values after iv administration.