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To investigate the hypothesis that the pharmacokinetics of imirestat, an aldose reductase inhibitor, are influenced by saturable binding to tissues, three experiments were done. (1) The nature of the dose dependence was characterized in rats. Two groups of nine adult male Sprague–Dawley rats received iv 14C-imirestat at doses of 2 or 8 mg/kg. Serial blood samples were obtained over 15 days. Volume of distribution at steady-state was significantly different between the high- and the low-dose groups (0.744 ± 0.103 1 and 1.10 ± 0.228 L, respectively). Clearance was independent of dose over this fourfold range (∼15 ml/hr). (2) The effect of either statil or AL3152, both aldose reductase inhibitors and potential competitors for aldose reductase binding, on the pharmacokinetics of a single 0.2-mg/kg iv dose of imirestat was assessed. A 2.4-mg/kg loading dose of statil was administered and a constant-rate infusion (56 µg/hr/kg) was begun 16 hr before imirestat. A 2-mg/kg loading dose of AL3152 and a constant-rate infusion (115 µg/kg/hr) were also administered 16 hr before imirestat. The infusions were maintained throughout the study. AL3152 administration decreased the imirestat steady-state volume of distribution by a mean of 63%. Statil administration decreased it by a mean of 39%. (3) The dosing regimen of the second study was repeated and, at two sampling times, nine tissues and plasma were obtained from four rats per sampling time for determination of imirestat tissue-to-plasma concentration ratio. The tissue/ plasma imirestat concentration ratio in the adrenals 24 hr after imirestat administration was 56.9 ± 20.0 in the imirestat group, 17.7 ± 1.27 in the statil-coadministered group, and 12.3 ± 2.59 in the AL3152-coadministered group. A similar trend of decrease in the ratios was observed in all tissues at both 24 and 168 hr. The results suggest that a saturable tissue binding phenomenon at least partially accounts for the nonlinear pharmacokinetics of imirestat.

1. The metabolism of the aldose reductase inhibitor, ALO1567, was studied in man. The major biotransformation pathway was aromatic hydroxylation followed by glucuronide conjugation. 2. Hydroxylation occurred at several positions on the fluorene ring. The major metabolite was identified as the 7-hydroxy analogue of ALO1567 and three minor metabolites were characterized as positional isomers of the 7-hydroxy metabolite. 3. Oxidative defluorination and metabolism on the hydantoin ring were also indicated as minor pathways. 4. The capacity of normal subjects to oxidize ALO1567 was indicated by the urinary ratio of the parent drug to the 7-hydroxy metabolite after daily oral administration of 100 mg and 200 mg of ALO1567. Most subjects having higher ALO1567 plasma concentrations showed higher ratios.

A sensitive and selective gas chromatographic-electron-capture assay was developed for the determination of the aldose reductase inhibitor imirestat in lens and plasma. The method involves solid-phase extraction of drug and internal standard from the plasma specimen or lens sample homogenate using "Baker"-10 SPE extraction columns followed by derivatization with pentafluorobenzyl bromide and further purification. Derivatives of drug and internal standard were separated on a fused-silica capillary column and analyzed using a 63Ni electron-capture detector. The limit of detection was 2.5 ng per lens or ml of plasma. The method was used to evaluate the pharmacokinetics of imirestat in human subjects and to quantitate imirestat in animal lens tissue following topical ocular administration.

The pharmacokinetics of imirestat were studied in healthy volunteers following single and multiple oral doses. After single doses of 20 to 50 mg, imirestat plasma concentrations declined with an apparent elimination half-life of 50 to 70 hr over the 168 hr in which levels were measured. However, with lower doses (2 to 10 mg), an initial rapid decline in drug concentration was followed by a very slow terminal elimination phase with plasma concentrations decreasing little over the 1 week of sampling. This resulted in a decrease in apparent t 1/2 with increasing dose, from 272 +/- 138 hr at 2 mg to 66 +/- 30 hr at 50 mg. During once-daily dosing of 2 to 20 mg/day for 4 weeks, mean steady-state imirestat concentration appeared to be dose proportional, although the time required to achieve steady state decreased with increasing dose. The mean effective half-life for accumulation ranged from 54 to 98 hr, suggesting that the very slow elimination of drug at low concentrations did not produce disproportionate accumulation of drug at these doses. Mean oral clearance was independent of dose, ranging from 30 to 45 ml/min. At the 2-, 5-, and 20-mg doses, one subject in each group had steady-state concentrations two- to fourfold greater than any of the other five subjects at the same dose, although the reason for this was not apparent from these data. The overall kinetic profile of these data was suggestive of dose-dependent pharmacokinetics resulting from nonlinear tissue binding of imirestat.(ABSTRACT TRUNCATED AT 250 WORDS)

To investigate the hypothesis that the pharmacokinetics of imirestat, an aldose reductase inhibitor, are influenced by saturable binding to tissues, three experiments were done. (1) The nature of the dose dependence was characterized in rats. Two groups of nine adult male Sprague-Dawley rats received iv 14C-imirestat at doses of 2 or 8 mg/kg. Serial blood samples were obtained over 15 days. Volume of distribution at steady-state was significantly different between the high- and the low-dose groups (0.744 +/- 0.103 l and 1.10 +/- 0.228 L, respectively). Clearance was independent of dose over this fourfold range (approximately 15 ml/hr). (2) The effect of either statil or AL3152, both aldose reductase inhibitors and potential competitors for aldose reductase binding, on the pharmacokinetics of a single 0.2-mg/kg iv dose of imirestat was assessed. A 2.4-mg/kg loading dose of statil was administered and a constant-rate infusion (56 micrograms/hr/kg) was begun 16 hr before imirestat. A 2-mg/kg loading dose of AL3152 and a constant-rate infusion (115 micrograms/kg/hr) were also administered 16 hr before imirestat. The infusions were maintained throughout the study. AL3152 administration decreased the imirestat steady-state volume of distribution by a mean of 63%. Statil administration decreased it by a mean of 39%. (3) The dosing regimen of the second study was repeated and, at two sampling times, nine tissues and plasma were obtained from four rats per sampling time for determination of imirestat tissue-to-plasma concentration ratio. The tissue/plasma imirestat concentration ratio in the adrenals 24 hr after imirestat administration was 56.9 +/- 20.0 in the imirestat group, 17.7 +/- 1.27 in the statil-coadministered group, and 12.3 +/- 2.59 in the AL3152-coadministered group.(ABSTRACT TRUNCATED AT 250 WORDS)

The pharmacokinetics of three aldose reductase inhibitors (ARIs) were evaluated in various species, including rat, dog, cynomolgus monkey, rhesus monkey, chimpanzee, and man. The three ARIs (AL01567, AL01576, and AL01750) were administered intravenously as a single dose to all species except rat, which was dosed orally with AL01750, and man, who was dosed orally with AL01567 and AL01576. Plasma drug concentrations were measured by HPLC or liquid scintillation spectrometry and various pharmacokinetic parameters (clearance, CL; Vd, volume of distribution; and t1/2) were calculated from the data. Overall the pharmacokinetics of the three compounds were quite similar, each being characterized by low CL, intermediate Vd, and long t1/2. For AL01576, mean CL ranged from 0.21 ml/min/kg in cynomolgus monkey to 0.91 ml/min/kg in dog, mean Vd from 0.66 liter/kg in cynomolgus monkey to 2.4 liters/kg in dog and man and mean t1/2 from 29 hr in dog to 72 hr in man. Mean CL of AL01567 ranged from 0.14 ml/min/kg in man to 1.4 ml/min/kg in dog, mean Vd from 0.45 liter/kg in rat to 3.5 liters/kg in dog and mean t1/2 from 22 hr in rhesus monkey to 63 hr in man. Mean CL of AL01750 ranged from 0.13 ml/min/kg in chimpanzee to 1.3 ml/min/kg in dog, mean Vd from 0.40 liter/kg in rat to 1.8 liters/kg in dog and mean t1/2 from 12 hr in rhesus monkey to 62 hr in chimpanzee. For all three drugs, CL and Vd corrected for body weight were quite similar in all species except dog, whose CL and Vd were two- to fourfold greater than the other animals.(ABSTRACT TRUNCATED AT 250 WORDS)

The pharmacokinetics of imirestat following topical ocular administration were evaluated in a series of studies in rabbits and dogs. Following single topical doses to both albino and pigmented rabbits, imirestat was subject to rapid uptake into the cornea followed by an initial rapid decline and then very slow elimination, with a t1/2 of approximately 130 hr. Drug was rapidly absorbed into aqueous humor, with concentrations declining to nondetectable levels by 12 hr. Imirestat was retained in the lens following topical dosing similar to that in cornea, with an apparent elimination t1/2 of 140 hr. Vitreous humor concentrations of drug were detectable for up to 72 hr after dosing. There was no apparent difference in the disposition of the drug between albino and pigmented rabbits. Bioavailability following topical dosing increased with dose, although not in a linear fashion. Formulation pH did not have an appreciable effect on ocular bioavailability. There was detectable systemic absorption following topical dosing, with plasma concentrations in rabbit being 50 to 75% of that observed following an equivalent intravenous dose. However, drug levels in the dosed eyes were significantly higher than in contralateral undosed eyes. Multiple dosing of imirestat for 6 weeks resulted in accumulation of drug in rabbit lens. Concentrations were higher in lens cortex than lens nucleus, with the time course for accumulation being different for the two. Our data suggest that imirestat penetrates into ocular tissue following topical dosing and is retained in lens and cornea, potential sites of action for the drug.

Many factors should be considered when choosing an appropriate population for a pharmacokinetic trial. Although there are some generalities that apply to most studies, each investigation must be judged separately, since the relevant considerations will vary depending on the particular study, the nature of the drug, and the population that will receive it for therapeutic benefit. Some of the most important information that is generated from pharmacokinetic studies concerns the pharmacokinetic variability among patients and the factors that can influence this variability under the conditions that the drug will be used. This information can best be obtained from a combination of baseline studies to define the variability within the patient population(s) and comparative studies to determine the impact of specific variables on the disposition of the drug and its pharmacokinetic variability. These data can provide valuable information to the clinician that can be used to individualize drug dosage and optimize therapy as well as to identify populations who may be at high risk of therapeutic failure or drug toxicity. It is our feeling that baseline studies in patients are necessary for understanding the pharmacokinetics of a drug, whereas the objectives of most comparative studies can be achieved using healthy volunteers. For most comparative studies, the data obtained from healthy volunteers will reflect what will occur in patients, especially if the variable of interest is drug absorption. This is particularly important when practical and ethical considerations preclude the use of patients. When considering studies in the elderly, one must decide whether the variable of interest may be influenced by age. Baseline pharmacokinetic studies in both patients and healthy volunteers should be conducted, whenever possible, before undertaking comparative studies in order that the data generated can provide a basis for choosing the population for subsequent, more rigorous studies. It is imperative to sufficiently understand the pharmacokinetics of the drug so that one can judge whether a given population will provide information that can be applied to patients who will use the drug for therapy. If the study objective can be successfully fulfilled without the need for a specific patient population, and if the data from healthy volunteers can be extrapolated to patients, practical considerations would suggest that healthy subjects should be used.

The multiple dose pharmacokinetics of isotretinoin and its major blood metabolite, 4-oxo-isotretinoin, were studied in 10 patients with cystic acne and 11 patients with various keratinization disorders. Blood samples were obtained at predetermined times following the first dose, interim doses and the final dose. Blood concentrations of isotretinoin and 4-oxo-isotretinoin were measured by a specific and sensitive HPLC method. A lag time was usually observed prior to the onset of absorption following oral administration of the drug in a soft elastic gelatin capsule. Absorption then proceeded rapidly and maximum blood concentrations usually occurred within 4 h of drug administration. The harmonic mean half-life for the elimination of isotretinoin by the cystic acne patients was approximately 10 h after the initial dose and did not change significantly following 25 days of 40 mg b.i.d. dosing. Steady-state blood concentrations remained relatively constant after the fifth day of dosing. The harmonic mean elimination half-life in the patients with various disorders of keratinization was about 16 h. The results of the 2 studies suggest that no significant changes in the pharmacokinetics of isotretinoin occur during multiple dosing and that the multiple dose pharmacokinetic profile is predictable and can be described using a linear pharmacokinetic model. This suggests that the steady-state concentrations of isotretinoin can be predicted from single dose data.

The extent of serum protein binding of AL01576, phenytoin (DPH), diazepam (DIAZ), and propranolol (PRO) was evaluated in a group of nondiabetic and a group of insulin-dependent diabetic subjects, as well as in streptozotocin-treated rats. Both serum glucose and glucosylated protein levels were elevated in the diabetic patient population (179 and 150% of control values, respectively). The mean free fractions (f p) of AL01576, DPH, and PRO were not statistically different for the two human groups. The DIAZ f p was slightly elevated (P < 0.05) in the diabetic patients (mean = 0.016) compared to the control group (mean f p = 0.014). An acute ( 20 days) diabetic rodent model was evaluated using Sprague–Dawley rats following streptozotocin administration (60 mg/kg i.p.). Both diabetic rat groups exhibited substantial increases in serum glucose, free fatty acids (FFA), and protein glucosylation compared to controls. The f p of AL01576 was increased in both the acute (mean = 0.248) and the chronic (mean = 0.202) condition compared to controls (mean = 0.163). The f p of DPH was also markedly increased in the acute (mean = 0.348) and the chronic (mean = 0.280) models compared to untreated controls (mean = 0.207). DIAZ and PRO binding was largely unaffected by the streptozotocin treatment. In vitro studies of purified human albumin suggest that a considerable degree of glucosylation would need to be present in diabetic serum before it would effectively alter drug binding. Our data suggest that only minor drug–serum binding changes occur in diabetic patients who are otherwise healthy and whose disease is well controlled.

The plasma concentration and antiarrhythmic effect data following multiple, ascending oral doses of cibenzoline in four patients with frequent premature ventricular contractions (PVCs) were analyzed using pharmacokinetic and pharmacodynamic modeling. Three methods of data analysis were tested in the analysis of the large amount of arrhythmia frequency data gathered during the study: as total-data set, average-data set, and grouped-data set. We have shown that the antiarrhythmic effect profile of the drug could be characterized by average data when a large number of PVC measurements are involved. Using the average-data sets, the plasma concentration of the drug at steady state could be correlated to the antiarrhythmic response using pharmacokinetic and pharmacodynamic modeling.

Single oral doses of cibenzoline were administered to eight healthy volunteers on two different occasions, once at 8.00 am and once at 10.00 pm, in a randomized crossover design with at least one week separating treatments. A fast was maintained for 12 hours prior to and for 2 hours after the morning dose and the subjects did not lie down for at least 12 hours after dosing. A standard dinner was eaten 3 hours prior to the evening dose, and a fast was maintained for 10 hours after dosing; the subjects laid down 2 hours after dosing for at least 6 hours. Blood was collected at specific times for 72 hours and the total volume of urine voided was collected through 72 hours. Cibenzoline concentrations in plasma and urine were measured by HPLC. Cibenzoline absorption was slower in 7 of the 8 volunteers following the evening dose relative to the morning dose. Mean +/- S.D. tmax for the evening dose was 2.6 +/- 0.5 hours compared to 1.7 +/- 0.8 for the morning dose. The corresponding mean +/- S.D. Cmax following the morning dose was 446 +/- 124 ng ml-1 compared to 402 +/- 114 ng ml-1 after the evening dose. The mean +/- S.D. AUC was 3328 +/- 1101 ng . h . ml-1 after the morning dose and 3561 +/- 1430 ng . h . ml-1 after the evening dose. The harmonic mean half-life was 7.4 hours after both treatments. These data indicated that the total amount of drug absorbed and the elimination rate constant of the drug had not varied between treatments.(ABSTRACT TRUNCATED AT 250 WORDS)

Effet de la concentration et du pH sur la fixation du AL 01576 sur l'albumine serique et sur la glycoproteine acide α1 humaine

Differences in the potency of intravenous (IV) and oral verapamil have recently been reported with the concentration-response curve for PR-interval prolongation being shifted further to the right following oral administration relative to IV administration. Using well-established pharmacokinetic models, a theoretic basis for these observations is presented. Simultaneous curve fitting of the IV and oral verapamil plasma concentration and PR-interval data to a single pharmacokinetic-pharmacodynamic model allowed prediction of differences in the pharmacodynamic potency of verapamil as a function of the rate of drug administration. These data indicate that the rate of input of drug into the systemic circulation can influence the rate and extent of entry of drug into an effect compartment, which in turn can result in different plasma concentration-response relationships.

The extent of serum protein binding of AL01576, phenytoin (DPH), diazepam (DIAZ), and propranolol (PRO) was evaluated in a group of nondiabetic and a group of insulin-dependent diabetic subjects, as well as in streptozotocin-treated rats. Both serum glucose and glucosylated protein levels were elevated in the diabetic patient population (179 and 150% of control values, respectively). The mean free fractions (fp) of AL01576, DPH, and PRO were not statistically different for the two human groups. The DIAZ fp was slightly elevated (P less than 0.05) in the diabetic patients (mean = 0.016) compared to the control group (mean fp = 0.014). An acute (less than 3 days) and chronic (greater than 20 days) diabetic rodent model was evaluated using Sprague-Dawley rats following streptozotocin administration (60 mg/kg i.p.). Both diabetic rat groups exhibited substantial increases in serum glucose, free fatty acids (FFA), and protein glucosylation compared to controls. The fp of AL01576 was increased in both the acute (mean = 0.248) and the chronic (mean = 0.202) condition compared to controls (mean = 0.163). The fp of DPH was also markedly increased in the acute (mean = 0.348) and the chronic (mean = 0.280) models compared to untreated controls (mean = 0.207). DIAZ and PRO binding was largely unaffected by the streptozotocin treatment. In vitro studies of purified human albumin suggest that a considerable degree of glucosylation would need to be present in diabetic serum before it would effectively alter drug binding. Our data suggest that only minor drug-serum binding changes occur in diabetic patients who are otherwise healthy and whose disease is well controlled.

The clinical pharmacokinetic profiles of two orally administered retinoids, isotretinoin and etretinate, are discussed and compared. The pharmacokinetic profile of isotretinoin is predictable and can be described using linear pharmacokinetic theory. The drug is rapidly absorbed following oral administration, is highly bound to plasma protein, and is metabolized to 4-oxo-isotretinoin. The apparent half-lives of elimination of isotretinoin and 4-oxo-isotretinoin following the oral administration of isotretinoin range from 10 to 20 hours and 24 to 29 hours, respectively. Steady-state pharmacokinetic profiles in patients are consistent with the single-dose pharmacokinetics in normal subjects. Following oral administration, etretinate undergoes significant first-pass biodegradation to its corresponding carboxylic acid; the acid appears rapidly in the circulation, often earlier than the parent drug, and its plasma concentration is usually comparable to, or greater than, that of the parent drug. The apparent elimination rates of drug and metabolite are similar (6-13 hours) following a single dose, suggesting that metabolite elimination may be formation-rate limited. During multiple dosing of etretinate, a very slow terminal elimination phase is observed which is not detected after single-dose administration. The prolonged half-life of this phase suggests accumulation in a deep tissue compartment. Differences between the two retinoids reflect their differing physicochemical properties.