Influence of ethanol and gender on methylphenidate pharmacokinetics and pharmacodynamics.

This study explores the hypotheses that: (1) ethanol will interact with dl-Methylphenidate (MPH) to enantioselectively elevate plasma d-MPH, and primarily yield l-ethylphenidate as a transesterification metabolite; (2) women will exhibit lower relative bioavailability of MPH than men; and (3) sex-dependent differences in subjective effects will exist. dl-MPH HCl (0.3 mg/kg) was administered orally 30 min before ethanol, 30 min after ethanol (0.6 gm/kg), or without ethanol, in a randomized, normal subject three-way crossover study of 10 men and 10 women. Pharmacokinetic parameters were compared. Subjective effects were recorded using visual analog scales. One subject was a novel poor MPH metabolizer whose data were analyzed separately. Ethanol after or before MPH significantly (P<0.0001) elevated the geometric mean for the maximum d-MPH plasma concentration (C(max) (+/-SD)) from 15.3 (3.37) ng/ml to 21.5 (6.81) and 21.4 (4.86), respectively, and raised the corresponding geometric mean for the area under the concentration-time curve values from 82.9 (21.7) ng ml/h to 105.2 (23.5) and 102.9 (19.2). l-MPH was present in plasma only at 1-3% of the concentration of d-MPH, except in the poor metabolizer where l-MPH exceeded that of d-MPH. The metabolite l-ethylphenidate frequently exceeded 1 ng/ml in plasma, whereas d-ethylphenidate was detected only in low pg/ml concentrations. Women reported a significantly greater stimulant effect than men when questioned "Do you feel any drug effect?" (P<0.05), in spite of lower mean plasma d-MPH area under the response-time curves in women. Ethanol elevates plasma d-MPH C(max) and area under the concentration-time curve by approximately 40% and 25%, respectively. If the poor metabolizer of MPH proves to be a distinct phenotype, determining the genetic mechanism may be of value for individualizing drug therapy. The more pronounced stimulant effects experienced by women have sex-based abuse liability implications.

Pharmacokinetics of chlorpheniramine, phenytoin, glipizide and nifedipine in an individual homozygous for the CYP2C9*3 allele.

Genetic polymorphisms in the cytochrome P450 (CYP) family are widely known to contribute to interindividual differences in the pharmacokinetics of many drugs. Several alleles for the CYP2C9 gene have been reported. Individuals homozygous for the Leu359 variant (CYP2C9*3) have been shown to have significantly lower drug clearances compared with Ile359 (CYP2C9*1) homozygous individuals. A male Caucasian who participated in six bioavailability studies in our laboratory over a period of several years showed extremely low clearance of two drugs: phenytoin and glipizide (both substrates of CYP2C9), but not for nifedipine (a CYP3A4 substrate) and chlorpheniramine (a CYP2D6 substrate). His oral clearance of phenytoin was 21% of the mean of the other 11 individuals participating in the study, and his oral clearance of glipizide, a second generation sulfonylurea structurally similar to tolbutamide, was only 188% of the mean of the other 10 individuals. However, his oral clearance of nifedipine and chlorpheniramine did not differ from individuals in other studies performed at our laboratories. An additional blood sample was obtained from this individual to determine if he possessed any of the known CYP2C9 or CYP2C19 allelic variants that would account for his poor clearance of the CYP2C9 substrates (phenytoin and glipizide) compared with the CYP3A4 (nifedipine) and CYP2D6 (chlorpheniramine) substrates. The results of the genotype testing showed that this individual was homozygous for the CYP2C9*3 allele and did not possess any of the known defective CYP2C19 alleles. This study establishes that the Leu359 mutation is responsible for the phenytoin and glipizide/tolbutamide poor metabolizer phenotype.

Bioequivalence, dose-proportionality, and pharmacokinetics of naltrexone after oral administration.

Healthy male volunteers (N = 24) participated in a four-way crossover study to compare the rate and extent of absorption of naltrexone after administration of 50 mg tablets as 50, 100, and 200 mg doses and a 10 mg/ml reference syrup. A high-performance liquid chromatographic method was employed to measure naltrexone and 6-beta-naltrexol in plasma and urine. Compared to the syrup, the 50 mg tablets were absorbed more slowly but equally well. There was excellent linearity between the administered dose and the area under the plasma concentration-time profile, as well as total urinary recovery of both drug and metabolite. The mean half-lives for naltrexone and beta-naltrexol were approximately 4 and 12 hours, respectively. The fraction of drug reaching the systemic circulation was estimated to be 5% of the administered dose because of extensive first-pass metabolism. Less than 1% of the dose was excreted in the urine as naltrexone after 48 hours, while 25% was recovered as unconjugated beta-naltrexol. The renal clearance of naltrexone and beta-naltrexol was approximately 127 ml/min and 283 ml/min, respectively. The total systemic clearance for naltrexone was approximately 94 L/hr.

A multiple-dose study of sustained-release theophylline and aminophylline.

This study evaluated the relative bioavailability of a sustained-release capsule of theophylline, an elixir of theophylline, and a sustained-release tablet of aminophylline. Twelve healthy, nonsmoking, adult male subjects received nine doses of each of the three products in a crossover study conducted over a ten-day period. Each dosage form contained approximately 250 mg of theophylline and was administered every eight hours. Concentrations of theophylline in the plasma at steady state demonstrated the equivalence of the three dosage forms in terms of the percent of drug absorbed, including the tablet which had exhibited reduced bioavailability in an earlier single-dose study of only five subjects. The steady-state average concentrations of theopylline in the plasma were 9.8 micrograms/ml, 10.3 micrograms/ml and 10.8 micrograms/ml for the tablet, capsulse, and elixir, respectively. The areas under the curves of the plasma level vs time for the three dosage forms were within 9 percent of each other. These data indicate that a significant reduction in fluctuations of the plasma level of theophylline was achieved with the two sustained-release dosage forms, compared to the elixir.

The influence of dosage form on papaverine bioavailability.

The bioavailability of sustained-release papaverine HCl dosage forms were compared to equivalent doses of the drug administered as an elixir and conventional compressed tablets to 12 healthy human subjects. Papaverine plasma levels were determined using a gas-chromatographic procedure. The drug was absorbed more rapidly and completely from the two nonsustained-release formulations. There was a large intersubject variability, and the plasma half-life of the drug was esstimated to be 1 hour. The area under the plasma level-time curve for the nine sustained-release products ranged from 18 to 64% relative to the area achieved by the papaverine elixir. It was concluded that the sustained-release dosage forms of papaverine included in each study group could be considered bioequivalent, but they exhibited inadequate bioavailability relative to either the elixir or the compressed tablet dosage form.

Serious bioavailability problems with a generic prolonged-release quinidine gluconate product.

A recently marketed prolonged-release quinidine gluconate tablet was compared with the innovator's tablet in a single-dose bioavailability study with 12 healthy male subjects. The extent of absorption of quinidine from the new marketed product was only 50 per cent of the innovator's product. This finding, as well as projections of steady-state plasma concentrations to be expected during multiple-dose administration, indicated a bioequivalence problem with medically significant implications. The data obtained in this study resulted in a Class I recall of the less completely absorbed product by the U.S. Food and Drug Administration.

Chloramphenicol clearance in infants.

Chloramphenicol clearance was evaluated over one dosing interval in 10 infants after at least 24 hours of therapy to evaluate dosage guidelines using a specific chemical assay. Serum samples were obtained prior to and at 1, 2, 4, and 6 hours after the start of a 20-minute infusion of 24 mg/kg chloramphenicol as the sodium succinate. The chemical assay used is technically simple and is specific for unesterified chloramphenicol. Peak serum concentrations ranged from 20.9 to 94.0 microgram/ml and occurred from 1 to 4 hours after infusion. Clearances ranged from 0.058 to 0.236 l./kg . hr and paralleled previously reported results using different assay methodology. The 4-hour serum chloramphenicol concentrations were significantly lower (P less than 0.05) in infants on phenobarbital. The currently recommended dose of chloramphenicol for severe infections, 100 mg/kg per day, is excessive in some infants. Widely divergent clearance rates prohibit uniform dosage guidelines so that serum level monitoring with an assay specific for chloramphenicol is essential.

Pharmacokinetic comparison of a once-daily and twice-daily theophylline delivery system.

The steady-state pharmacokinetics of a formulation of a 24-hour extended-release theophylline preparation (Uni-Dur) were compared with a twice-daily formulation (Theo-Dur) in healthy volunteers. Eighteen healthy, adult, male volunteers received both treatments (600-mg dose of Uni-Dur every morning for 5 doses or 300 mg every 12 hours for 10 doses of Theo-Dur) in a randomized, two-way crossover design with no washout period between treatments. Blood samples were collected just before doses 3, 4, and 5 of Uni-Dur and before doses 5, 7, and 9 of Theo-Dur, as well as at 2-hour intervals for 24 hours following doses 5 of Uni-Dur and doses 9 and 10 of Theo-Dur. The mean serum theophylline concentration-time curves were similar for both formulations from 2 to 18 hours postdose, and the maximum serum theophylline concentrations were comparable (7.66 micrograms/mL for Uni-Dur compared with 7.78 micrograms/mL for Theo-Dur). Fluctuations in serum theophylline concentrations were greater with Uni-Dur (139 +/- 85% compared with 72 +/- 25% normalized to trough serum concentrations; 77 +/- 22% compared with 53 +/- 13% normalized to average steady-state serum concentrations). Based on the area under the curves, the extent of absorption of Uni-Dur was 91.42 +/- 14.24% of Theo-Dur. These findings suggest that the clinical response in patients treated with once-daily Uni-Dur may be equivalent to Theo-Dur given every 12 hours. Furthermore, because of the similar serum concentration over time profiles of the two formulations, it is unlikely that additional monitoring of serum levels during a conversion will be necessary.

Replacement of dehydroepiandrosterone enhances T-lymphocyte insulin binding in postmenopausal women.

OBJECTIVE: To demonstrate bioavailability of 3 weeks of oral micronized DHEA and to delineate changes induced on insulin sensitivity, morphometric indexes, and lipoprotein profiles. DESIGN: Oral micronized DHEa (50 mg/d) was administered in 3-week treatments to 11 postmenopausal women in a prospective, placebo-controlled, randomized, blinded, crossover trial with an interarm washout. After dose (23 hour) serum DHEA, DHEAS, T, and cortisol levels were measured, as were fasting lipoproteins, oral glucose tolerance tests (OGTT), T-lymphocyte insulin binding and degradation, and urine collagen cross-links. Morphometric changes were determined by hydrostatic weighing. RESULTS: Dehydroepiandrosterone sulfate, DHEA, T, and free T increased up to two times premenopausal levels with treatment. Fasting triglycerides declined; no change in collagen cross-links or morphometric indexes was noted. Oral glucose tolerance test parameters did not change, but both T-lymphocyte insulin binding and degradation increased with DHEA. CONCLUSION: Fifty milligrams per day of oral DHEA gives suprahysiologic androgen levels; 25 mg/d may be more appropriate. Dehydroepiandrosterone enhanced tissue insulin sensitivity and lowered serum triglycerides. Rationale is provided for postmenopausal replacement therapy with this androgen.

Urinary excretion of methenamine and formaldehyde: evaluation of 10 methenamine products in humans.

The urinary excretion of both methenamine and formaldehyde was measured for 48 hr after the oral administration of 10 different methenamine products to 10 human subjects in a crossover study. The following dosage forms were evaluated: a tablet of methenamine base, a methenamine hippurate tablet, and eight products containing methenamine mandelate, including six enteric-coated tablets, a suspension, and a granule dosage form. The nonenteric-coated dosage forms were absorbed more rapidly, based on maximum excretion rates that occurred within 3 hr after dosing. The enteric-coated tablets, which were designed not to release methenamine until reaching the intestinal tract, exhibited maximum excretion rates that did not occur until 7-17 hr after dosing. There were no significant differences (p greater than 0.05) among products in terms of total excretion of free formaldehyde in the urine. However, large differences (p less than 0.05) were noted among products for urinary recovery of total methenamine, with the amount of administered dose recovered ranging from 16 to 83%.

Circadian rhythms in theophylline disposition: simulations and observations in the dog.

A constant-rate iv infusion of aminophylline approaching steady state in four dogs was used to investigate a circadian rhythm in theophylline disposition. A significant circadian rhythm (p less than 0.05, group cosinor analysis) was observed for serum theophylline concentrations and for the urinary excretion rates of theophylline and 3-methylxanthine. The phase relationship of the observed circadian rhythms in urinary pH to circadian changes in serum theophylline concentrations were supportive of a circadian rhythm in renal clearance of theophylline. Computer simulations indicated that circadian changes in serum theophylline concentration and urinary excretion of theophylline and its metabolites could be accounted for by a circadian rhythm in theophylline renal clearance and metabolism to 3-methylxanthine. A circadian rhythm in theophylline volume of distribution could not be totally dismissed as potentially having some effect on disposition. The timing of food intake is hypothesized to play a role in synchronizing the observed rhythm in serum theophylline concentrations.

Circadian rhythm in theophylline disposition during a constant-rate intravenous infusion of aminophylline in the dog.

The disposition of theophylline in three dogs was determined during a 48-h constant-rate intravenous infusion of aminophylline. A systematic fluctuation in serum theophylline concentrations was observed over a 24-h period, which appeared to be characteristic of a circadian rhythm. Neither assay variability nor fluctuations in the infusion pump rate could account for the observed variations in the serum concentrations. It was concluded that the changes in the theophylline concentrations were the result of a circadian rhythm in theophylline disposition.

Bioavailability of dyphylline and dyphylline-guaifenesin tablets in humans.

A six-way-crossover bioavailability study was conducted with twelve healthy male volunteers to evaluate the relative bioavailability of three tablet formulations containing dyphylline and three tablet formulations containing dyphylline-guaifenesin. Each subject was administered two tablets of each product with greater than or equal to 3 d separating each dose. Blood samples were obtained just prior to each dose and at 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, and 10.0 h following each dose. An HPLC method was used to assay dyphylline in the serum. The mean tmax ranged from 0.6 to 1.0 h for the six products. The mean values for Cmax differed by 29%, and the AUC values differed by less than 8%. It was noted that the dyphylline-guaifenesin products exhibited a lower bioavailability than the products which only contained dyphylline. It was concluded that the three combination products were bioequivalent, as were the three dyphylline products.

Bioavailability of chlorothiazide tablets in humans.

A urinary excretion bioavailability study was conducted in 12 healthy male subjects to evaluate three 250-mg and three 500-mg chlorothiazide tablet products. The study was a crossover design, and urine samples were collected 1, 2, 3, 4, 6, 8, 12, and 24 hr after administration of each dose. The resulting data were statistically analyzed for significant differences in cumulative percent of dose excreted at each sampling time, total drug recovery after 24 hr, maximum excretion rate, and time of maximum excretion rate. No statistically significant differences were found between the three 250-mg tablets tested. The urinary drug recovery after administration of one of the 500-mg products was significantly (p less than 0.05) lower than that from the other two 500-mg tablets. The total mean recovery from each product ranged from only 11 to 20%, indicating that in general chlorothiazide was not well absorbed following oral administration. Attempts at correlating the urinary excretion data with the dissolution rate determinations were not successful.

Relative bioavailability of meprobamate tablets in humans.

The relative bioavailability of 400-mg meprobamate tablets manufactured by 11 different firms was evaluated in two groups of healthy male subjects. Each group of six subjects received a reference standard product and five test products given at 1-week intervals. Plasma meprobamate concentrations at 1, 2, 3, 4, 6, 8, 10, 24, and 32 hr after dosing were determined using a GLC assay. Analysis of variance of the plasma level--time profiles revealed no statistically significant differences between any of the products in terms of plasma levels at the various sample times, time of peak plasma level, peak plasma level, and area under the plasma level--time curve. It was concluded that the 11 400-mg products could be considered bioequivalent.

Bioavailability of 11 sulfisoxazole products in humans.

Single lots of 11 commercially available 500-mg sulfisoxazole tablets were evaluated in vitro and in vivo. All products tested met USP XVIII specifications for weight variation and product assay. However, three products failed to meet the USP XVIII dissolution requirement. The only statistically significant difference observed between the 11 products was a lower peak plasma level exhibited by one product. No useful correlation was observed between the in vivo and in vitro studies for the dosage forms tested.

Bioavailability of sulfadiazine solutions, suspensions, and tablets in humans.

A four-way crossover sulfadiazine bioavailability study was conducted in 16 normal healthy male volunteers. The subjects were divided into groups of eight. Each group received four different oral dosage forms of sulfadiazine at 1-week intervals: a solution as a reference, a suspension, and two different tablets. All dosage forms were equivalent to 500 mg of sulfadiazine. Blood samples were obtained at 0, 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, 25.0, 33.0, and 49.0 hr. Analysis of variance indicated no statistically significant difference (p more than 0.05) between the dosage forms in terms of area under the plasma level--time curve, peak plasma concentration, and time of peak plasma concentration. In both groups, there were differences between products at isolated sampling times. It was concluded that the four tablet formulations of sulfadiazine exhibited bioavailability characteristics equivalent to those of the solution and the suspension.

Bioavailability of propylthiouracil in humans.

Single lots of five commercially available 50-mg propyl-thiouracil formulations were evaluated in vitro and in vivo. Each product met the USP XIX specifications for drug content, content uniformity, and disintegration time. However, major differences were noted among products in their rate and extent of dissolution. Statistically significant differences (p less than 0.05) were observed in vivo among the drug formulations at all but one of the sampling times, as determined from crossover blood level studies in 12 healthy male volunteers. The differences among the areas under the plasma level-time curves for the various products were not statistically significant. No statistically significant correlations were found between the in vitro and in vivo parameters studied.

Absorption of phenobarbital from tablets and elixir.

A three-way crossover study was conducted with 24 healthy male volunteers to determine the relative bioavailability of four different 100-mg phenobarbital tablets compared with a reference elixir. Each subject received two of the tablets and the elixir at 30-d intervals. Blood samples were collected daily for 19 d after each dose. Plasma phenobarbital concentrations achieved with the five dosage forms differed by less than 20% within 2-3 h after dosing. The extent of absorption for all dosage forms, as determined from area under the plasma concentration-time profiles, were within 10% of each other. The peak plasma concentration was the greatest and the time to peak concentration was the shortest for the elixir. One of the tablets exhibited a time to peak concentration of 8.6 h, which was significantly longer than any of the other dosage forms. The time to peak concentration correlated with the percent of drug dissolved in 60 min, as determined in 0.1 M HCl, using the USP XX paddle method at 50 rpm.