Dietary saccharin kinetics.

Six adult female subjects who use saccharin-containing products in their diet were asked to take divided equal doses of saccharin every 6 hr to maintain their average daily intake for 3 days. At the end of this period, each subject took a single dose that was equal to one divided dose. Saccharin concentrations in plasma and urine samples were used to assess the kinetic profile. Saccharin absorption was rapid with maximum concentrations in plasma in 0.5 to 1.0 hr. Maximum plasma concentrations and areas under the plasma concentration-time curves were proportional to dose. Renal clearance exceeded glomerular filtration rate in all cases and approximated renal plasma flow when corrected for the saccharin free fraction in plasma. Mean elimination half-life was 7.5 hr and mean apparent volume of distribution was 264 l. The kinetic parameters indicate that saccharin is distributed as a function of lean rather than total body mass (suggesting that saccharin does not distribute into body fat). This observation, together with data from studies in animals, suggests that there may be one or more high-retention compartments for saccharin.

Salivary excretion and pharmacokinetics of sulfapyridine after sulfasalazine.

The concentrations of sulfapyridine (SP) and N4-acetylsulfapyridine (AcSP) in the plasma and saliva of 5 healthy male adults (3 slow and 2 rapid acetylators) were determined as a function of time after a single 2.0-gm oral dose of sulfasalazine (salicylazosulfapyridine). SP absorption commenced 3.5 to 6 hr after sulfasalazine administration and occurred slowly (apparent absorption t1/2s ranged from 1.6 to 5 hr) irrespective of acetylator phenotype. Appreciable differences existed between slow and rapid acetylators with respect to the biologic t1/2 and total body clearance of SP. SP concentrations in the saliva correlated well with those in the plasma. The saliva:plasma concentration ratio for SP was 0.559 +/- 0.027 (mean of 5 subjects +/- SE) and was dependent of plasma concentration and saliva pH. The mean saliva:plasma concentration ratio for AcSP was lower (0.246 +/- 0.056), consistent with the pH-partition hypothesis, and showed considerably more intrasubject and intersubject variation than the ratio for SP. These findings suggest that measurement of SP concentrations in the saliva may be a convenient, noninvasive method for monitoring indirectly the steady-state plasma (serum) concentrations of SP in patients with ulcerative colitis or Crohn's disease who are receiving sulfasalazine.

In utero-exposure to saccharin: a threat?

In-utero or immediate post-utero exposure of rats to saccharin results in an increased incidence of bladder tumors when compared to post-weaning exposure only. We studied 6 human mother-infant pairs following maternal intake of saccharin close to delivery. High performance liquid chromatography revealed the presence of saccharin in all 6 newborn cord sera as well as their mothers' sera and urine. This constitutes the first report of placental transfer of saccharin in humans. Despite the relative weakness in carcinogenicity of saccharin, this in-utero exposure, coupled with ex-utero exposure, may possibly contribute to an increased incidence of neoplasms.

A preliminary report on the pharmacokinetics of saccharin in man: single oral dose administration.

The pharmacokinetics of saccharin were studied in two human subjects. One male and one female subject ingested a single 100 mg oral dose of saccharin. Absorption was fast and the elimination half-lives were 1.2 and 6.6 hours for the male and female subject, respectively. Approximately 85% of the oral dose was recovered in the urine as intact saccharin and renal clearance approximated renal plasma flow when corrected for the unbound fraction of saccharin in plasma. Saccharin elimination appears to be related to previous saccharin ingestion, suggesting a high-retention compartment.

Relative systemic availability of sulfapyridine from commercial enteric-coated and uncoated sulfasalazine tablets.

The absorption of sulfapyridine after a single 2.0-Gm oral dose of sulfasalazine, the drug of choice in the treatment of inflammatory bowel disease, as commercial uncoated and enteric-coated and uncoated tablets was evaluated in four healthy male adults. The peak plasma concentration of sulfapyridine after the enteric-coated tablets occurred at 20 hours on the average (compared to 14 hours for the uncoated tablets) and was only 50% of that attained from the uncoated tablets (P less than 0.05). The low relative extent of systemic availability of sulfapyridine from the enteric-coated tablets (65.5 +/- 6.3 per cent, mean +/- S.E.) compared to uncoated tablets may be due to absorption rate-dependent presystemic metabolism, since the relative extent of sulfapyridine absorption was 92.7 +/- 6.2 per cent compared to uncoated tablets. These findings suggest that enteric-coated and uncoated tablets of sulfasalazine are not bioequivalent. It remains to be determined whether the clinical efficacy of sulfasalazine from enteric-coated tablets is affected.

Effect of meals on the kinetics of etretinate.

Eight healthy men received 100 mg oral doses of etretinate separated by two-week washout periods in an open, randomized, crossover study. Etretinate was administered during a complete fast, with a standard high fat breakfast, a standard high carbohydrate breakfast, and 16 ounces of whole milk. Plasma samples were obtained at specific times over a 48-hour period. Plasma concentrations of etretinate as well as two of its major metabolites were determined by a specific, reverse-phase, high-performance liquid chromatography method. Plasma concentrations of etretinate were greater when administered with a high fat meal and whole milk compared to ingestion with a high carbohydrate meal or during a complete fast. In contrast, there was no increase in the plasma concentrations of the active metabolites following any of the meals. These data indicate that chronic dosing of etretinate with milk or a high fat meal compared with fasting conditions will result in higher concentrations of etretinate, which may ultimately lead to higher metabolite concentrations.

Time course of free and N4-acetylated sulfapyridine concentrations in the plasma and saliva of man after sulfasalazine (salicylazosulfapyridine) administration: preliminary findings.

The time course of free and N4-acetylated sulfapyridine (SP) concentrations in the saliva and whole plasma was determined in a healthy male volunteer after a single 2.0 g oral dose of salicylazosulfapyridine (SASP) as four-500 mg commercial, uncoated tablets. The mean (+/- S.D.) plasma: saliva concentration ratios for free and acetylated SP was 2.04 (+/- 0.24) and 3.12 (+/-0.43), respectively, and were independent of plasma concentration and saliva pH. The elimination half-lives of SP and N4-acetyl SP could be determined from either salivary or plasma concentration-time data. These preliminary results suggest that measurement of saliva concentrations of free and acetylated SP may be a convenient, noninvasive method for monitoring indirectly the plasma concentrations of SP and acetyl SP in patients treated with SASP and for determining acetylator phenotype.

Overall pharmacokinetics during prolonged treatment of healthy volunteers with digoxin and beta-methyldigoxin.

Five healthy volunteers received digoxin 0.4 mg or beta-methyldigoxin 0.4 mg i.v., daily for 14 days, in a randomized cross-over arrangement. By monitoring minimal plasma concentrations during multiple dosing, it was found that the steady state pharmacokinetics of digoxin and beta-methyldigoxin could be estimated even better by a one-compartment than by a two-compartment model. The following mean parameters were calculated: the half life of digoxin of 1.54 +/- 0.31 days was significantly shorter than the half life of 2.29 +/- 0.34 days for beta-methyldigoxin. The distribution volume of 807 +/- 187 liters for digoxin was not significantly larger than the 735 +/- 227 liters for beta-methyldigoxin. Renal digoxin clearance of 191 +/- 25 ml/min was significantly higher than both the renal clearance of beta-methyldigoxin of 111 +/- 23 ml/min and also the creatinine clearance, which indicates tubular secretion of digoxin. There was a 2.8-fold accumulation of beta-methyldigoxin injected once a day, which was significantly higher than the 1.80-fold accumulation of digoxin.

Determination of chlorprothixene and its sulfoxide metabolite in plasma by high-performance liquid chromatography with ultraviolet and amperometric detection.

This communication describes a rapid, sensitive and selective method for the assay of chlorprothixene and its sulfoxide metabolite in human plasma, using reversed-phase high-performance liquid chromatography. Alkalinized plasma was extracted with heptane--isoamyl alcohol (99:1), after addition of thioridazine as the internal standard. The residue obtained after evaporation of this extract was chromatographed on a cyano column, using acetonitrile--0.02 M potassium dihydrogen phosphate pH 4.5 (60:40) as the mobile phase with ultraviolet (229 nm) detection. Quantitation was based on peak height ratios over the concentration range of 5.0-50.0 ng/ml for both compounds with 85% and 90% recovery for chlorprothixene and its sulfoxide metabolite, respectively, using a 1.0-ml plasma sample. The assay chromatographically resolves chlorprothixene and the sulfoxide metabolite from the N-desmethyl metabolite, which can only be semi-quantitated owing to low and variable recoveries. The method was used to obtain plasma concentration versus time profiles in two subjects after oral administration of 100 mg of chlorprothixene suspension and in two additional subjects following overdosages of chlorprothixene estimated to exceed several hundred milligrams. These analyses demonstrated that the sulfoxide metabolite is the predominant plasma component following therapeutic administration and overdosages. High-performance liquid chromatography with oxidative amperometric detection with the glassy carbon electrode was also evaluated. Although this procedure demonstrated comparable sensitivity and precision to ultraviolet detection for the analysis of chlorprothixene and N-desmethyl chlorprothixene, the sulfoxide metabolite could not be measured with high sensitivity (less than 100 ng/ml) owing to endogenous interferences. Hence the utility of this alternative assay technique is limited.

Effect of food on cibenzoline bioavailability.

Eighteen healthy adult volunteers received 160 mg oral capsule doses of cibenzoline in an open-label, four-way randomized crossover study designed to determine the influence of food on cibenzoline pharmacokinetics. Cibenzoline was administered 1 h prior to, with, and 1 h following a standard breakfast as well as under fasting conditions. There was no change in any bioavailability parameter when the data following drug ingestion 1 h prior to food were compared to the fasted state. Bioavailability parameters obtained when drug was taken during the meal or 1 h after the meal suggested that the rate of absorption was slightly decreased in the presence of food, while the extent of absorption was unaltered. The decreased absorption rate in the presence of food is not expected to be of clinical significance. The presence of food is not expected to affect the bioavailability of cibenzoline to the extent of clinical significance.

Dose dependent pharmacokinetics of midazolam.

The pharmacokinetics of midazolam and 1-hydroxymethylmidazolam were investigated following oral administration of 7.5, 15 and 30 mg doses of midazolam in solution to 12 healthy subjects. Compared to the 7.5 mg dose, the Cmax and AUC parameters of both midazolam and 1-hydroxymethylmidazolam increased proportionally after the 15 mg dose and more than proportionally after the 30 mg dose. The t1/2 for midazolam remained relatively constant between the 7.5 and 15 mg doses whereas it increased slightly but significantly after the 30 mg dose. These data indicated that the pharmacokinetics of midazolam and 1-hydroxymethylmidazolam were linear between the 7.5 and 15 mg oral dose range. However, after the 30 mg dose, the systemic availability of midazolam and the AUC for 1-hydroxymethylmidazolam appeared to be greater than that anticipated from the lower doses, possibly due to saturation of midazolam first-pass metabolism. This is not expected to have any clinical significance under the conditions of therapeutic use.