Urinary Recovery Of Unchanged Drug Research Articles

Pharmacokinetics of metformin in the rat: assessment of the effect of hyperlipidemia and evidence for its metabolism to guanylurea.

Metformin pharmacokinetics are highly dependent upon organic cationic transporters. There is evidence of a change in its renal clearance in hyperlipidemic obese patients, and no information on its metabolic fate. To study some of these aspects, the influence of poloxamer 407 (P407)-induced hyperlipidemia on metformin pharmacokinetics was assessed. Control and P407-treated adult male rats were administered 30 mg/kg metformin intravenously (i.v.). The pharmacokinetic assessments were performed at 2 time points, 36 and 108 h, following the intraperitoneal dose of P407 (1 g/kg). mRNA and protein expressions of cationic drug transporters were also measured. There was no evidence of a change in metformin pharmacokinetics after i.v. doses as a consequence of short-term hyperlipidemia, and a change in transporter mRNA but not protein expression was observed in the P407- treated rats 108 h after P407 injection. Urinary recovery of unchanged drug was high (>90%) but incomplete. Presumed metabolite peaks were detected in chromatograms of hepatocytes and microsomal protein spiked with metformin. Comparative chromatographic elution times and mass spectra suggested that one of the predominant metabolites was guanylurea. Hyperlipidemia by itself did not affect the pharmacokinetics of metformin. Guanylurea is a putative metabolite of metformin in rats.

Pharmacokinetics, safety, and tolerability following single-dose migalastat hydrochloride (GR181413A/AT1001) in healthy male Japanese subjects

Objective:Fabry disease is a rare X-linked disease caused by mutations to the GLA gene, resulting in a deficiency of the lysosomal enzyme alpha-galactosidase A. This study evaluated the pharmacokinetics, safety, and tolerability of ascending single doses of oral migalastat hydrochloride (HCl), an investigational drug, in healthy Japanese volunteers.Methods:In this phase I, randomized, placebo-controlled, single-blind, ascending single-dose, cross-over study, migalastat HCl (50 mg, 150 mg, or 450 mg) or placebo was administered orally to 14 fasting male Japanese volunteers (aged 20–55 years) on 4 non-consecutive days. Main plasma and urine pharmacokinetic end-points included maximum observed plasma concentration (Cmax), time to Cmax (tmax), area under the plasma concentration–time curve (AUC), apparent terminal-phase half-life (t1/2), urinary recovery of unchanged drug, renal clearance, and percentage of drug excreted in urine. Safety end-points included adverse events, clinical signs and symptoms (e.g., hematology, chemistry, and urinalysis), vital signs (blood pressure and heart rate), and 12-lead electrocardiogram.Clinical trial registration number:ClinicalTrials.gov registration identifier is NCT01853852.Results:Median tmax of migalastat was 3.0–3.5 h. Migalastat HCl concentrations declined relatively rapidly, with a mean t1/2 of 3.2–4.0 h. The amount of migalastat HCl recovered in the urine and the percentage of migalastat HCl excreted unchanged over 24 h were consistent (∼45–50%) across the dose range. The AUC and Cmax of migalastat HCl were dose proportional from 50–450 mg. Safety results were similar to those observed in non-Japanese populations.Conclusions:This study demonstrated that ascending single doses of migalastat HCl (50 mg, 150 mg, 450 mg) are absorbed at a moderate rate and eliminated relatively rapidly, with a safety profile consistent with that observed in non-Japanese populations. These results confirm the dose-proportional pharmacokinetics of migalastat HCl from 50–450 mg. This study was limited by a small subject population and a short-term follow-up.

Influence of a bacterial lipopolysaccharide on the pharmacokinetics of tobramycin in rats.

The effects of Klebsiella pneumoniae O3 lipopolysaccharide on the renal handling and distribution characteristics of the aminoglycoside tobramycin were investigated in rats. Tobramycin (2 mg kg-1) and inulin (100 mg kg-1) were administered intravenously 2 h after administration of 50, 250 or 500 micrograms kg-1 lipopolysaccharide. Lipopolysaccharide delayed the disappearance of tobramycin from plasma in a dose-dependent manner. A dose-dependent decrease in systemic clearance of tobramycin was observed, although the elimination rate constant and fraction of urinary recovery of unchanged drug were not significantly different in any group. Lipopolysaccharide significantly decreased the central compartment volume of distribution of tobramycin, but did not influence the steady-state volume of distribution. A dose-related increase in the ratio of the rate constant of transfer to the peripheral compartment to the rate constant of transfer from peripheral compartment to central compartment was observed. The glomerular filtration rate was significantly decreased by pretreatment with 250 micrograms kg-1 lipopolysaccharide and the clearance ratio was decreased by 20%, indicating that lipopolysaccharide increases the tubular reabsorption of tobramycin. Our findings suggest that K. pneumoniae O3 lipopolysaccharide modifies the glomerular filtration rate and tubular reabsorption without change in the terminal half-life and that drug distribution characteristics from the rapidly-distributing compartment to the peripheral compartment were altered without expansion of the extracellular fluid volume.

Adefovir dipivoxil for the treatment of HBeAg-positive chronic hepatitis B: a review of the major clinical studies

Adefovir dipivoxil (ADF) is an orally bioavailable prodrug of adefovir, a phosphonate nucleotide analog of adenosine monophosphate [1]. Adefovir has potent in vitro activity against hepadnaviruses, retroviruses and herpesviruses [2–5]. The intracellular compound, adefovir diphosphate, acts as a competitive inhibitor and chain-terminator of hepatitis B virus (HBV) replication mediated by HBV DNA polymerase [6]. Ten mg daily of adefovir has recently been licensed for the treatment of chronic hepatitis B in adults with evidence of HBV replication. The efficacy of ADF was investigated in patients with compensated liver disease and evidence of HBV replication; in patients failing lamivudine therapy, including posttransplantation patients, patients with compensated and decompensated liver failure and patients co-infected with human immunodeficiency virus (HIV). Several of these studies have been published. The data in HBeAg-positive patients is reviewed in this manuscript.

Pharmacokinetics of gabapentin in subjects with various degrees of renal function

The pharmacokinetics of oral gabapentin (400 mg) was studied in normal subjects and in subjects with various degrees of renal function. Sixty subjects participated in this three-center study. None of the subjects were receiving hemodialysis. Plasma and urine samples were collected for up to 264 hours after dosing, and concentrations of gabapentin were determined by high performance liquid chromatography. Apparent oral plasma clearance (CL/F) and renal clearance (CLR) of gabapentin decreased and maximum plasma concentration, time to reach maximum concentration, and half-life values increased as renal function diminished. Gabapentin CL/F and CLR were linearly correlated with creatinine clearance. Total urinary recovery of unchanged drug was comparable in all subjects, indicating that the extent of drug absorption was unaffected by renal function. There was no evidence of gabapentin metabolism even in subjects with severe renal impairment. In summary, impaired renal function results in higher plasma gabapentin concentrations, longer elimination half-lives, and reduced CL/F and CLR values. Based on pharmacokinetic considerations, it appears that the dosing regimen of gabapentin in subjects with renal impairment may be adjusted on the basis of creatinine clearance.

Pharmacokinetic studies of CP-74,667, a new quinolone, in laboratory animals

The pharmacokinetics of CP-74,667 (7-(8'-methyl-3',8'-diazabicyclo[3.2.1]oct-3'-yl)-1-cyclopropyl-6- fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid) were studied following oral or parenteral administration in mice, rats, rabbits, dogs, and cynomolgus monkeys. The mean peak levels of CP-74,667 in serum following a single oral dose of 20 mg/kg of body weight were similar in all species, with a range of 3.7 micrograms/ml in mice to 5.6 micrograms/ml in dogs. In contrast, elimination half-lives were species dependent, with mean values of 2.1, 1.8, 4.5, 7.8, and 13.1 h in mice, rats, rabbits, dogs, and monkeys, respectively. The oral bioavailability of CP-74,667 was 100% in dogs and monkeys, as determined by intravenous-oral crossover experiments. The maximum concentration of drug in serum and area under the concentration-time curve (AUC) of CP-74,667 in dogs were proportional to dose over the range of 5 to 40 mg/kg. Accumulation of drug in serum was observed following the administration of four once-a-day doses of 7.1 mg/kg in monkeys (mimicking a 500-mg human dose), with significant increases in half-life, maximum and minimum concentrations of drug in serum, and AUC. The good tissue penetration of CP-74,667 suggested by a volume of distribution in excess of 2 liters/kg in dogs and monkeys was confirmed by tissue distribution studies with the same species, which demonstrated tissue concentrations (except for those in brain tissue) greater than 1.45 times higher than corresponding levels in serum. The mean urinary recoveries of unchanged drug were 17.7% in rats, 7.8% in monkeys, and 4.9% in dogs. Metabolism studies in dogs, following intravenous dosing, indicated that renal excretion of CP-74,667-related materials accounted for 41.6% of the administered dose, while biliary recoveries accounted for 6.8%. The CP-74,667 N-oxide metabolite was the primary drug-related material eliminated via renal excretion (37.2% of dose). The pharmacokinetics of CP-74,667 describe a quinolone with complete oral absorption, linear pharmacokinetics, a long elimination half-life, and wide distribution into tissues.

Nonlinear disposition of intravenous 2',3'-dideoxyinosine in rats.

The pharmacokinetics of 2',3'-dideoxyinosine (ddI) were examined in rats given intravenous doses of 8, 40, or 200 mg/kg. The concentrations of ddI in whole blood and plasma were identical. The concentration decline was multiexponential, with mean half-lives of 2 and 20 min for the first and second phases, respectively. At the highest dose, a slower third phase with a half-life of 56 min was observed. The total-body clearances were 99, 77, and 37 ml/min-kg for the 8, 40, and 200 mg/kg doses. The steady-state volume of distribution showed a trend for a decrease with increasing doses, but the difference was not statistically significant. Twenty-four-hour urinary recovery of unchanged drug for the three doses was similar at about 20%, suggesting that a major fraction of the dose was metabolized. Urinary excretion of ddI metabolite, hypoxanthine, accounted for less than 5% of the dose. Renal and metabolic clearances decreased with increased doses. ddI was metabolized in blood; the addition of inorganic phosphate, a cosubstrate in phosphorylase-mediated nucleoside catabolism, enhanced the degradation by about fourfold. In summary, these data indicate equal distribution of ddI in the extracellular and intracellular spaces in blood, its enzymatic degradation in blood, and nonlinear elimination kinetics.

A study of the pharmacokinetics and pharmacodynamics of nifedipine in combination with atenolol

This double-blind randomized, crossover study was undertaken to determine the pharmacokinetic properties of nifedipine retard and atenolol when given separately, as a free or a fixed combination, compared with placebo in 15 healthy male volunteers. There was no difference between the three atenolol formulations in time to maximum blood concentration or elimination half-life. The fixed combination showed significant differences in both maximum observed blood concentrations (+16 per cent) and total area under the curve (+16 per cent) compared to atenolol alone. Urinary recovery of unchanged drug from the fixed combination was also slightly increased but the difference was not statistically significant. Furthermore, statistical evaluation of the plasma pharmacokinetics of nifedipine retard and urinary recovery of nifedipine metabolite showed that all three formulations were indistinguishable. Thus, it is concluded that the fixed combination of nifedipine and atenolol is bioequivalent to the free combination and that the bioavailability of both drugs in the fixed combination is equivalent to that of the single entities.

Effect of mequitazine on the pharmacokinetics of theophylline in asthmatic patients

The effect of an oral anti-allergic drug, mequitazine, on the pharmacokinetics of theophylline has been investigated in seven asthmatic patients. They received chronic theophylline therapy (a sustained-release theophylline tablet 200-400 mg b.d. at 12 h intervals) and coadministered mequitazine 6 mg for 3 weeks. Plasma theophylline concentration-time curves and the urinary excretion of theophylline and its major metabolites before and after coadministration of mequitazine were compared. No significant change in the pharmacokinetic parameters of theophylline or in the urinary recovery of unchanged drug and its metabolites was observed. Thus, mequitazine did not influence the pharmacokinetics of theophylline and it should be safe for coadministration to asthmatic patients on chronic theophylline therapy.

Absorption and disposition kinetics of chlorothiazide in protein‐calorie malnutrition

The influence of dietary protein deficiency on the absorption and disposition kinetics of chlorothiazide was investigated in male Sprague-Dawley rats fed for 4 weeks on a 23 per cent (control) or a 5 per cent (low) protein diet ad libitum. Chlorothiazide in plasma and urine was determined by a sensitive and specific HPLC assay. Following an intravenous dose of 10 mg kg-1 chlorothiazide, there was a significant decrease in the total plasma clearance (Cl) per kg of body weight from 1.80 +/- 0.15 to 1.29 +/- 0.15 l h-1 kg-1 and apparent steady-state volume of distribution from 0.65 +/- 0.13 to 0.38 +/- 0.07 l kg-1 in the protein-deficient rats. However, no significant difference was found in the two groups of animals with respect to mean residence time (MRT) and free fraction of drug in plasma. The mean harmonic half-life was increased from 72 to 91 min in the protein-deficient rats. The urinary recovery of unchanged chlorothiazide in 48 h was essentially complete in both groups of animals. The absorption of chlorothiazide, as assessed by the mean urinary recovery of unchanged drug after oral administration, was 66 per cent and 68 per cent in normal and protein-deficient rats, respectively.

Pharmacokinetics of famotidine in elderly patients with and without renal insufficiency and in healthy young volunteers

The pharmacokinetics of the H2-receptor antagonist famotidine, after oral administration of a 20 mg tablet, has been studied in 10 elderly patients with normal renal function (CLCR greater than or equal to 59 ml.min-1, Mean = 80 ml.min-1), 5 elderly patients with renal insufficiency (CLCR less than or equal to 38 ml.min-1, Mean = 15 ml.min-1), and 6 healthy young volunteers. Elimination half-life in the elderly patients with renal insufficiency was significantly prolonged compared to the elderly patients with normal renal function and the young volunteers. The correlation coefficient between creatinine clearance and the elimination rate constant of famotidine was 0.672. Mean urinary recovery of unchanged drug up to 24 h in the young volunteers was 44%. The mean renal clearance of famotidine in the young volunteers (270 ml.min-1) was substantially greater than the creatinine clearance, 128 ml.min-1, which suggests the possibility of tubular secretion of famotidine.

Pharmacokinetics of xamoterol after intravenous and oral administration to volunteers.

The pharmacokinetics of xamoterol, a beta-adrenoceptor partial agonist under clinical evaluation for the treatment of mild to moderate heart failure, have been studied in 12 healthy male subjects. They received 14 mg i.v. and oral doses of 50 and 200 mg as a tablet and 200 mg as a solution in a 4 way cross-over design. After i.v. dosing the elimination half-life was 7.7 h, the total body clearance was 224 ml.min-1 and the volume of distribution at steady-state (Vss) was 48 l. Sixty-two percent of the dose was recovered unchanged in urine. After oral doses, the absolute bioavailability of xamoterol was shown to be 5% irrespective of whether the dose was administered as a tablet or solution. Peak plasma concentrations occurred at about 2 h for the tablet dose and slightly earlier (1.4 h) for the solution. Peak plasma concentration, AUC and urinary recovery of unchanged drug increased in proportion to dose. The apparent elimination half-life after oral doses (16 h) was significantly longer than that observed after an intravenous dose. Despite the low bioavailability, the degree of inter-subject variability of oral bioavailability was small probably indicating that the controlling factor is the hydrophilic nature of the molecule rather than extensive first pass metabolism or poor dissolution of xamoterol from the tablet formulation.

Single‐dose pharmacokinetics and bioavailability of famotidine in man. Results of multicenter collaborative studies

Pharmacokinetics and bioavailability of famotidine, a new H2-receptor antagonist, were investigated in healthy subjects in five clinical studies. Linear pharmacokinetics were observed following either intravenous or oral administration. Plasma clearance averaged 463 ml min-1. Renal clearance averaged 310 ml min-1, which exceeded the glomerular filtration rate. Renal excretion was the major route of elimination. Urinary recovery of unchanged drug following intravenous administration was about 67 per cent. Famotidine plasma half-life was approximately 2.6 h. Oral absorption was incomplete. The bioavailability averaged 43 per cent of the dose.

Pharmacokinetic profile of cefixime in man.

Cefixime is an orally absorbed third generation cephalosporin with a broad spectrum of activity against Gram-positive and Gram-negative bacteria and is highly resistant to beta-lactamase degradation. In general serum and urinary concentrations of cefixime achieved after recommended daily doses are well above the minimal inhibitory concentrations at 90% for indicated microorganisms. The pharmacokinetics of cefixime were determined in adult and pediatric subjects. In general the half-life of the drug is about 3 to 4 hours and is not dependent on dose. The drug is not extensively bound to serum proteins; the free fraction is about 31% and is concentration-independent. The absolute bioavailability, based on comparisons of area under the serum concentration-time curve values after 200-mg intravenous, 200-mg oral solution, and 200- and 400-mg capsule doses, ranged from 40 to 52%, showing a comparable bioavailability for cefixime at single 200- and 400-mg oral doses. In a dose proportionality study, over an oral dose range of 200 to 2000 mg, peak serum concentration (Cmax) and area under the concentration-time values increased linearly but were not directly proportional with dose. Upon multiple dosing for 2 weeks on a 400-mg daily or 200-mg twice a day regimen, serum concentrations and urinary recovery of unchanged drug were similar for each group, and there was no drug accumulation. Peak serum concentration and area under the concentration-time curve values after a 400-mg dose were almost double those after a 200-mg dose. All formulations of cefixime were bioequivalent to an oral reference solution at doses of 200 and 400 mg.(ABSTRACT TRUNCATED AT 250 WORDS)

Enprofylline pharmacokinetics in children with asthma.

The pharmacokinetics of intravenous enprofylline has been studied in 8 children with asthma. The mean plasma half-life of enprofylline (1.0 h) was considerably shorter than that previously reported in adults. The half-life determined from log urine excretion rate data was identical to the plasma half-life, so urine excretion could be used as a non-invasive method to study the elimination rate. As in adults, urinary recovery of unchanged drug averaged 89%, and the volume of distribution, Vz, averaged 0.58 l/kg. Clearance was higher in children than in adults when calculated per kg body weight, but not when calculated per m2 body surface area. The dosage of enprofylline in children would be more accurate if calculated in proportion to surface area rather than to body weight. Data agree with published information on creatinine clearance, which, adjusted for body surface area, stays constant from the age of 3 years until early adult life.

Pharmacokinetics of ticarcillin and clavulanic acid (timentin) in relation to renal function.

The disposition of coadministered ticarcillin (3 g/1.73 m2) and clavulanic acid (100 mg/1.73 m2) was examined after a 30-min infusion in 24 noninfected subjects with various degrees of renal function. Noncompartmental pharmacokinetic parameters for the individual compounds were determined from plasma concentrations and urinary excretion rates. All clearances (total, renal, and nonrenal) and urinary recoveries of unchanged drug were found to be linearly related to creatinine clearance (CLCR). The steady-state volume of distribution (9.9 and 12.9 liters for ticarcillin and clavulanic acid) approximated the extracellular fluid space and was not related to CLCR. The half-lives increased with reduced renal function and ranged from 56 to 392 min for ticarcillin and 26 to 266 min for clavulanic acid. The clearances of both drugs decreased proportionately with reduction in renal function, facilitating dosing adjustments based on CLCR. Calculations of expected steady-state maximum and minimum concentrations in plasma using constant doses and an extended dosing interval related to CLCR further rationalized use of the 30:1 drug combination ratio for all patients.

Bioavailability and diuretic effect of furosemide during long-term treatment of chronic respiratory failure.

The bioavailability and diuretic effect of furosemide 40 mg administered orally for at least 6 months have been compared in patients with chronic respiratory failure and in healthy controls. The mean urinary recovery of unchanged drug was 11.5 mg and 9.41 mg in 24 h after pre- and postprandial administration to 10 patients, whereas the recovery was 14.4 mg in 10 healthy subjects. The diuretic effect, in terms of urine flow and sodium ion excretion in the 6 h after administration, was also less in patients than in healthy subjects. This was ascribed to the lower bioavailability of furosemide in patients, based on the urinary recovery of unchanged drug, and not to a lower level of response to furosemide than in healthy subjects. The mean absolute bioavailability of furosemide in 6 patients was 41.3% and 63.4%, respectively, calculated from unchanged drug and total drug (unchanged plus glucuronide conjugate). Approximately 53.9% of the dose of furosemide was excreted as the glucuronide conjugate after oral administration, and 34.2% after i.v. injection in the 6 patients. In 3 of the 6 patients studied, a distinct first-pass effect for glucuronidation of furosemide was observed after oral administration. In another study, the mean glucuronide fraction recovered in 24-h urine was 20.7% and 7.3% (p less than 0.01) in 38 patients and 12 healthy subjects, respectively. The fraction in urine was not affected by changing the dose of furosemide from 20 to 120 mg. The lower bioavailability in patients as compared to healthy subjects is ascribed to enhanced glucuronidation and incomplete drug absorption.

Cimetidine kinetics during resuscitation from burn shock.

Severely burned patients suffer from rapidly changing metabolic and hemodynamic abnormalities that could alter drug kinetics. The kinetics of cimetidine, commonly used in the prophylaxis of acute stress erosions, were studied during fluid resuscitation of 11 patients with mean burn sizes of 45% total body surface area. Six patients were studied after the completion of fluid resuscitation. Total clearance, steady-state volume of distribution, and cimetidine t1/2 did not change between the early period after burn and after fluid resuscitation, but before the completion of fluid resuscitation patients had lower renal and greater nonrenal cimetidine clearance than after resuscitation. The increase in nonrenal cimetidine clearance resulted in decreased urinary recovery of unchanged drug, 50.7 +/- 14% during fluid resuscitation and 81.0% +/- 6% after resuscitation.

Pharmacokinetics of ceftizoxime in subjects with various degrees of renal function.

The pharmacokinetics of ceftizoxime (FK-749) were studied in 20 volunteers with various degrees of renal function. Creatinine clearances ranged from zero to 157 ml/min per 1.73 m2. One gram of ceftizoxime was administered by a 30-min drip infusion, and blood and urine samples were collected for up to 48 h after drug administration. For volunteers with a creatinine clearance of greater than or equal to 80 ml/min per 1.73 m2 (group I), the mean half-life was 1.65 h, whereas for volunteers with a creatinine clearance of less than 10 ml/min per 1.73 m2 (group IV), the half-life was 34.7 h. The volume of distribution at steady state (Vdss) and the volume of distribution area (Vdarea) were calculated for each group and ranged from 0.377 to 0.263 and 0.421 to 0.264 liters/kg for groups I and IV, respectively. Total body clearance of ceftizoxime correlated with creatinine clearance (r = 0.953), and the mean urinary recovery of unchanged drug in normal volunteers was 72.4%. A 4-h hemodialysis procedure reduced serum ceftizoxime concentrations by approximately 52%; however, serum concentrations at 48 h after drug administration were still greater than 10 micrograms/ml in dialysis subjects. By using the relationship between total body clearance of ceftizoxime and creatinine clearance, a nomogram was developed to assist in the administration of ceftizoxime to patients with renal dysfunction.

Species Differences in the Urinary Excretion of the Novel Primary Amine Conjugate: Tocainide Carbamoyl O-β-D-Glucuronide

The metabolism of the antiarrhythmic drug tocainide (I) has been shown previously to occur via a novel pathway involving the addition of carbon dioxide to the primary amine nitrogen of I followed by conjugation with glucuronic acid. The product of this reaction, tocainide carbamoyl O-β3-D-glucuronide (II), the principal metabolite of I in humans, has been found to cyclize under strongly basic conditions to form 3-(2,6-xylyl)-5-methylhydantoin (III). Thus, evidence for the existence of II can bē obtained by two different procedures: conversion of II to III in the presence of strong base and by hydrolysis of II with β-glucuronidase. The principal purpose of the present investigation was to identify suitable species for studies of the mechanism involved in the forrnation of II, as well as to find an animal model suitable for toxico-logical evaluation of tocainide and structurally related compounds. Eight animal species were examined to identify those capable of metabolizing I into II. The fraction of an intraperitoneal dose excreted in urine as II was estimated by measurement of tocainide released by β-glucuronidase mediated hydrolysis of urine and by the quantitation of III formed after alkalinization of urine samples. Urinary recovery of unchanged drug ranged from 9.5% of the dose in the gerbil to 48.7% in the cat. The percent of the dose excreted in urine as acid hydrolyzable conjugates ranged from <1% in the gerbil to a mean of 13% in the rabbit. Guinea pigs, dogs, cats, rabbits, and pigtail monkeys excreted amounts of II ranging from 0.2 to 2.4% of the dose. Thus, none of the species appeared to be a suitable model for the study of the mechanism of formation of II because of the quantitative insignificance of this pathway.