Use of midazolam urinary metabolic ratios for cytochrome P450 3A (CYP3A) phenotyping.

Midazolam (MDZ) total clearance (ClT) is widely used for cytochrome P450 3A (CYP3A) phenotyping, but requires up to eight blood samples. This study was conducted to compare the use of midazolam ClT to use of a midazolam urinary metabolic ratio for CYP3A phenotyping. Ten male and 10 female subjects received i.v. midazolam 0.025 mg/kg eight times over a 4-month period at approximately 2-week intervals. The first six phenotyping measures were used to estimate baseline CYP3A activity, then subjects received the moderate CYP3A inhibitor fluvoxamine 150 mg/day for the last 4 weeks (two phenotyping visits) of the study. Serial blood samples were obtained for calculation of ClT. Urine was collected for 6 h following each midazolam dose. Midazolam, 1'-hydroxymidazolam (1-OHMDZ), and 4-hydroxymidazolam were measured in plasma and urine by liquid chromatography with tandem mass spectrometry (LC/MS/MS). Analysis of 148 samples from 20 subjects revealed a weak overall correlation between the urinary ratio of 1-OHMDZ/MDZ to midazolam ClT of r(s) = 0.372 (P = 0.0001). There was no correlation when examining either baseline samples or fluvoxamine-inhibited samples alone (r(s) = 0.101, P = 0.289 and r(s) = 0.266, P = 0.123, respectively). The median (range) urinary ratio decreased significantly with fluvoxamine [219 (141-409) versus 127 (50-464); P = 0.005] and to a similar extent to the midazolam ClT (-33.6% versus -42.4%, respectively; P > 0.05). Median urinary recovery of the i.v. midazolam dose varied between 1.4% and 53% and was significantly lower in samples collected while patients were receiving fluvoxamine (34.3% versus 23.1%; P= 0.0004). Based on these results, although this midazolam urinary ratio was not very reflective of baseline CYP3A activity, it may be a useful indicator of CYP3A inhibition.

Effect of fluvoxamine therapy on the activities of CYP1A2, CYP2D6, and CYP3A as determined by phenotyping.

OBJECTIVE: To determine the effect of 150 mg/day fluvoxamine on the activities of CYP1A2, CYP2D6, CYP3A, N-acetyltransferase-2 (NAT2), and xanthine oxidase (XO) by phenotyping with caffeine, dextromethorphan, and midazolam. METHODS: Oral caffeine (2 mg/kg), oral dextromethorphan (30 mg), and intravenous midazolam (0.025 mg/kg) were administered to 10 white male volunteers every 14 days for 4 months and to 10 white premenopausal female volunteers during the midfollicular and midluteal phases of the menstrual cycle for 4 complete cycles (8 total phenotyping measures). The first 6 phenotyping measures were used to establish baseline activity. Subjects were given 150 mg/day fluvoxamine for the fourth month or cycle of the study. Enzyme activity for CYP1A2, CYP2D6, NAT2, and XO was expressed as urinary metabolite ratios. Midazolam plasma clearance was used to express CYP3A activity. RESULTS: No difference between baseline and weeks 2 and 4 of fluvoxamine therapy was observed for NAT2 or XO metabolite ratios. For CYP1A2, CYP2D6, and CYP3A phenotypes, significant differences existed between baseline and fluvoxamine therapy. For CYP1A2, the mean urinary metabolite ratio (+/-SD) was 7.53 +/- 7.44 at baseline and 4.30 +/- 2.82 with fluvoxamine ( P = .012). Mean CYP2D6 molar urinary dextromethorphan ratios before and after fluvoxamine therapy were 0.00780 +/- 0.00694 and 0.0153 +/- 0.0127, respectively (P = .011). Midazolam clearance decreased from 0.0081 +/ 0.0024 L/min/kg at baseline to 0.0054 +/- 0.0021 L/min/kg with therapy (P = .0091). For CYP1A2, CYP2D6, and CYP3A, fluvoxamine therapy changed the phenotyping measures by a median of -44.4%, 123.5%, and -34.4%, respectively. CONCLUSIONS: We concluded that fluvoxamine may cause significant inhibition of CYP1A2, CYP2D6, and CYP3A activity. This metabolic inhibition may have serious implications for a variety medications.

Quantification of 3-month intraindividual variability and the influence of sex and menstrual cycle phase on CYP3A activity as measured by phenotyping with intravenous midazolam.

OBJECTIVE: Intraindividual variability and the effects of sex and menstrual cycle phase on CYP3A activity were evaluated by phenotyping with use of midazolam as the probe drug. METHODS: Midazolam (0.025 mg/kg) was administered intravenously to 10 white male volunteers every 14 days for 3 months and to 10 white premenopausal female volunteers during the midfollicular and midluteal phases of the menstrual cycle for 3 complete cycles. Serum was collected for a 6-hour period, and enzyme activity was represented by midazolam plasma clearance. RESULTS: No difference in clearance was observed during the menstrual cycle phases. Mean +/- SD midazolam clearance was 0.00816 +/- 0.00252 L/min/kg during the midfollicular phase and 0.00818 +/- 0.00224 during the midluteal phase (P = .96). When the menstrual cycle phases were combined, mean midazolam clearance in women was 0.00817 +/- 0.00235 L/min/kg. Mean male midazolam clearance was 0.00766 +/ 0.00167 L/min/kg. There was no difference in midazolam clearance between men and women (P = .68). Coefficients of variation (CV%) for the 6 phenotyping visits were calculated and the median midazolam clearance CV% (25th to 75th percentile) was 9.75% (8.40% to 11.5%). CONCLUSIONS: Because no significant differences in midazolam clearance were noted between menstrual cycle phases or between sexes, pharmacokinetic and clinical investigations of CYP3A activity in adults may not require stratification on the basis of menstrual cycle phase or sex.

GMP criteria for retest and failure analysis. Handling out-of-specification results in the pharmaceutical quality control laboratory.

The Food and Drug Administration's current Good Manufacturing Practices guidelines for the inspection of pharmaceutical quality control laboratories stress the need for explicit standard operating procedure's requirements for retesting criteria and the investigation of specification failures. Out-of-specification results are best handled through a priori procedures for the evaluation of their validity. These procedures should also specify the degree of retesting or resampling permitted. Initial investigations should focus on uncovering apparent laboratory-related or sampling errors. Should this initial investigation prove inconclusive, an expanded investigation should be conducted to uncover any less conspicuous cause, which could include process or operator-dependent as well as analytical errors. A schematic approach to controlling retesting through a rigorous policy of investigating failures, limiting retest analyses, and documenting and reporting all results is described.

The absorption of oral micronized progesterone: the effect of food, dose proportionality, and comparison with intramuscular progesterone.

OBJECTIVES: To examine the effects of food ingestion and administered dose on the absorption of oral micronized P (Utrogestan; Besins-Iscovesco, Paris, France) and to compare the bioavailability of intramuscular versus oral routes of administration. DESIGN: Prospective, randomized, open label crossover protocol with 7 days between dosages. SETTING: Academic institution. PARTICIPANTS: Fifteen normal postmenopausal women. INTERVENTIONS: All subjects participated in three separate protocols: [1] micronized P (200 mg) or placebo under fasting or nonfasting conditions once daily for 5 days; [2] micronized P (100, 200, or 300 mg) once daily under fasting conditions for 5 days; and [3] micronized P (200 mg) or intramuscular P (50 mg in oil) administered once daily for 2 days. MAIN OUTCOME MEASURES: Serum P concentrations were measured in all groups. RESULTS: Concomitant food ingestion increased the area under the serum P concentration versus time curve (AUC0 to 24) and the maximum serum P concentration (Cmax) without affecting time to maximum serum concentration (Tmax) (P < 0.05). Micronized P absorption and elimination were first-order processes and exhibited dose-independent pharmacokinetics between 100 and 300 mg. After intramuscular P, Cmax was higher and Tmax occurred later compared with the oral P preparation. Oral P had lower relative bioavailability (8.6%) than intramuscular P. CONCLUSIONS: Absorption of micronized P was enhanced twofold in the presence of food. Both absorption and elimination were dose-independent, dose proportionality being confirmed. Bioavailability of the oral P was approximately 10% compared with intramuscular P.

Theophylline pharmacokinetics: effect of continuous versus intermittent cimetidine i.v. infusion.

The comparative effects of continuous versus intermittent cimetidine infusion on theophylline pharmacokinetics were evaluated in 12 nonsmoking healthy male volunteers. Each subject received aminophylline 0.9 mg/kg/hr over 6 hours alone (control) and in random order at 1 week intervals, in combination with intermittent cimetidine (300 mg IV over 15 minutes every 6 hours) and continuous cimetidine (50 mg/hr IV) infusions. Both cimetidine regimens were administered for a total of 50 hours. Serial plasma samples were obtained and assayed for theophylline by HPLC. No significant differences existed in mean theophylline clearance and mean volume of distribution among control, intermittent or continuous cimetidine regimens; the power was greater than 80% to detect a 30% change in clearance. Only a minor difference in theophylline half-life between control and continuous cimetidine infusion (7.59 +/- 2.52 vs. 9.05 +/- 3.17 hr; P less than .05) was observed. These findings do not support a clinically significant interaction between IV aminophylline and cimetidine administered IV either as a low dose continuous infusion or as an intermittent infusion.

Comparative evaluation of the effects of isradipine and diltiazem on antipyrine and indocyanine green clearances in elderly volunteers.

Calcium antagonists have been shown to depress hepatic enzymes and accelerate hepatic blood flow. This study was designed to compare the effects of two calcium antagonists, isradipine and diltiazem, on antipyrine and indocyanine green (ICG) clearances in the elderly. Eighteen elderly subjects (aged 65 to 80 years) received either isradipine (5 mg every 12 hours), diltiazem (90 mg every 8 hours), or placebo (every 12 hours) for 4 days. On the third day after the study treatment, a 0.5 mg/kg dose of ICG was administered. Blood samples were obtained over 20 minutes for HPLC determination of ICG plasma concentrations. Ten minutes later, subjects ingested 1.2 gm antipyrine. Blood samples were obtained over 48 hours for HPLC determination of antipyrine plasma concentrations. Mean +/- SD antipyrine clearance after diltiazem (0.0258 +/- 0.0065 L/hr/kg) was significantly lower than that observed after isradipine (0.0334 +/- 0.0098 L/hr/kg) or placebo (0.0329 +/- 0.0082 L/hr/kg). Antipyrine clearance after isradipine was not significantly different from that after placebo. Mean +/- SD ICG clearances after diltiazem (9.17 +/- 1.35 ml/min/kg) or isradipine (9.57 +/- 1.82 ml/min/kg) were significantly higher than that observed after placebo (8.06 +/- 1.45 ml/min/kg). These findings suggest that diltiazem, but not isradipine, affects hepatic enzyme activity in the elderly. Both agents accelerate ICG clearance, a marker of hepatic blood flow.

Norfloxacin does not alter warfarin's disposition or anticoagulant effect.

Drug interactions related to inhibition of hepatic drug metabolism have been identified for some fluoroquinolone antibiotics. This study was designed to investigate whether the fluoroquinolone norfloxacin at the usual clinical dosage interacts with the anticoagulant agent warfarin. Ten healthy male subjects were administered a single oral dose of 30 mg warfarin sodium alone or during multiple-dose treatment with norfloxacin, 400 mg bid, in a randomized, crossover fashion. Plasma warfarin concentrations and prothrombin times were measured for 6 days after each of the two warfarin doses. The pharmacokinetic parameters of warfarin were comparable in the absence and presence of norfloxacin, including no significant differences in warfarin's elimination half-life, apparent total clearance, apparent volume of distribution, or peak plasma concentration. Norfloxacin also had no significant effect on the anticoagulant effect of warfarin, as assessed by the area under the prothrombin time versus time curve and the maximum response for prothrombin time. The lack of pharmacokinetic or pharmacodynamic interaction observed in this study suggests that a clinically important interaction of norfloxacin and warfarin is unlikely to occur in patients requiring both drugs.

Characterization of dexamethasone binding in normal and uremic human serum.

The purpose of this study was to examine the extent and linearity of dexamethasone binding over a wide concentration range in normal and uremic serum. Tritiated dexamethasone was added to both untreated and charcoal-treated pooled normal serum and to pooled uremic serum to produce concentrations similar to those attained therapeutically (10-1000 ng/mL). Protein binding was determined by equilibrium dialysis at 37 degrees C. Dexamethasone serum binding was linear over the entire range of concentrations for each set of pooled serum. The mean (+/- SD) percent bound (mean +/- SD) for dexamethasone was similar for untreated (75.1 +/- 3.6 percent) and charcoal-treated (77.3 +/- 3.5 percent) normal serum. Dexamethasone binding (69.2 +/- 1.8 percent, p less than 0.05) and serum albumin concentrations (39.9 vs. 55.1 mmol/L) were significantly less in uremic vs. normal serum, respectively. These results suggest that (1) the binding of dexamethasone is linear and occurs primarily to albumin, with little or no binding to corticosteroid-binding globulin; (2) endogenous cortisol does not compete with dexamethasone for protein binding sites; and (3) steroid pharmacokinetics may be altered in uremic patients due to the 24 percent higher free fraction of dexamethasone in this population.

Pharmacokinetics and pharmacodynamics of labetalol in elderly and young hypertensive patients following single and multiple doses.

Several physiologic changes accompany the aging process and may alter the pharmacokinetics and pharmacodynamics of drugs given to elderly patients. The primary purpose of the present investigation was to compare the pharmacokinetics of labetalol in young and elderly hypertensive patients. Limited data regarding the pharmacodynamics of labetalol in each of these age groups were also evaluated. Ten young (age 32-48 yrs) and nine elderly (age 60-68 yrs) patients with essential hypertension were evaluated after the first and last doses of a 15-day regimen of labetalol. The young group received 200 mg orally at 9:00 P.M. and 9:00 A.M.; the elderly group received 200 mg once daily at 9:00 P.M. No significant differences in the mean (SD) apparent oral clearance of the drug existed between groups after the first [4.8 (1.9) and 4.3 (1.2) L/hr/kg] and final [4.4 (2.2) and 3.4 (1.0) L/hr/kg] doses of labetalol. No changes in any pharmacokinetic values for labetalol were detected as a function of age. Changes in standing blood pressure and heart rate after the first and last doses were generally similar between the young and elderly hypertensives. Labetalol was effective and well tolerated in both groups.

Effects of age on the elimination of labetalol.

Labetalol is an alpha 1- and beta-adrenergic antagonist currently used in the treatment of hypertension. Studies which have evaluated the effects of age on its pharmacokinetics have yielded conflicting results. The purpose of this study is to comprehensively re-evaluate the effect of age on the elimination of labetalol. Data were obtained from 4 single-dose and 3 multiple-dose studies of the pharmacokinetics of the drug. An analysis of covariance was performed on the single-dose data to determine whether the type of subject evaluated (normotensive vs hypertensive), type of assay methodology used and/or age were significant factors affecting labetalol clearance estimates. A similar covariance procedure was used for the multiple-dose data, to assess whether the type of subject, duration of treatment and/or age were significant variables affecting labetalol elimination. Subsequent to the analysis of covariance, linear regression and correlation analysis was used to evaluate the effects of age on labetalol clearance. A modest though significant relationship was observed between the apparent oral clearance of the drug and age; it appeared slightly stronger when clearance was normalised for bodyweight. No relationship was found following multiple doses of the drug. Hence, age does not appear to be a significant factor affecting the oral clearance of labetalol, particularly in individuals receiving the drug in the long term.

Clinical evaluation of a benzofuroquinolizine alpha 2-adrenoceptor antagonist.

The pharmacodynamics of MK-912, a benzofuroquinolizine alpha-adrenoceptor antagonist, were evaluated in healthy male volunteers. Eight subjects were treated with single oral doses of 0.1, 1.0, and 2.0 mg MK-912 and with a placebo in a four-period, double-blind, balanced, crossover study. Hemodynamic effects were observed with the 2.0 mg dose of MK-912 (peak increase from baseline in systolic and diastolic blood pressure +/- SEM, 14.8/9.2 +/- 2.9/2.1 mm Hg; peak increase in heart rate, 6.3 +/- 2.1 beats/min; p less than 0.05 versus placebo). Plasma concentrations of 3-methoxy-4-hydroxyphenylglycol (MHPG, a catecholamine metabolite) were increased 29% +/- 7% and 40% +/- 10% above baseline 2 hours after administration of 1.0 and 2.0 mg MK-912, respectively (p less than 0.01 compared with placebo). A modest dose-dependent reduction (5% to 10%) in fasting plasma glucose concentration was observed 1/2 to 1 hour after administration of 1.0 and 2.0 mg MK-912 (p less than 0.05 compared with placebo), without significant change in plasma insulin values. MK-912 was well tolerated, although it did have a mild anxiogenic effect. MK-912 is a potent, orally active agent with a pharmacologic profile consistent with alpha 2-adrenoceptor antagonism.

Comparative evaluation of the effects of labetalol, verapamil and diltiazem on antipyrine and indocyanine green clearances.

The effects of labetalol, diltiazem and verapamil on antipyrine and indocyanine green clearance were evaluated in a placebo-controlled, repeated measures evaluation. Twelve healthy subjects received either labetalol (200 mg every 12 hours), diltiazem (90 mg. every 8 hours), verapamil (80 mg every 8 hours), or placebo (every 12 hours) for 4 days. On the morning of Day 3 immediately following their dose, the subjects assumed the supine position for 90 minutes, after which time a 0.5 mg/kg dose of indocyanine green was administered. Blood samples were obtained serially over a 20 minutes period for indocyanine green plasma concentration determinations by HPLC. Ten minutes later, subjects ingested a 1.2 Gm. dose of antipyrine and blood samples were obtained over a 48 hour period for antipyrine plasma concentration determinations by HPLC. A 2 week washout period separated treatment sequences. Mean (SD) antipyrine clearance (L/hr/kg) following diltiazem [0.028 (0.010)] and verapamil [0.030 (0.012)] treatment was significantly lower than that observed following placebo [0.039 (0.012)]. Antipyrine clearance following labetalol administration [0.033 (0.010)] was not significantly different from that observed following placebo, diltiazem or verapamil administration. No effects of these drugs on indocyanine green clearance could be detected.

Trimethoprim inhibition of the renal clearance of procainamide and N-acetylprocainamide.

To test the effect of trimethoprim (an antibiotic commonly administered with sulfamethoxazole) on the disposition of the antiarrhythmic procainamide hydrochloride and its active metabolite N-acetylprocainamide, 10 healthy men received 1 g of procainamide hydrochloride orally on two occasions, coadministered with placebo or trimethoprim (100 mg twice a day for 2 days before and then 200 mg with the procainamide dose). Trimethoprim decreased the mean (+/- SD) renal clearance by 45% after the dose of procainamide was administered (487 +/- 129 vs 267 +/- 123 mL/min) and that of N-acetylprocainamide by 26% (275 +/- 78 vs 192 +/- 82 mL/min) compared with placebo. The mean area under plasma concentration--time curve 0 to 12 hours after dosing increased 39% for procainamide (19.8 +/- 4.8 vs 27.6 +/- 7.2 mg.h/L) and 27% for N-acetylprocainamide (9.1 +/- 2.1 vs 11.4 +/- 2.8 mg.h/L). The corrected QT electrocardiographic interval at 2 hours after the procainamide dose was 0.40 +/- 0.02 second with placebo and 0.43 +/- 0.03 second with trimethoprim. Trimethoprim may increase procainamide and N-acetylprocainamide plasma concentrations, resulting in increased pharmacodynamic response apparently caused by the competition for renal tubular cationic secretion.

Ranitidine-induced changes in the renal and hepatic clearances of procainamide are correlated.

Ranitidine, procainamide and its active N-acetyl metabolite (NAPA) are renally secreted bases which can compete for carrier-mediated transport processes. The effect of ranitidine on the disposition of procainamide and NAPA was evaluated in 13 healthy men. Subjects were randomized to receive p.o. procainamide (1000 mg) alone (base line) and after p.o. ranitidine, 150 mg twice a day for 4 days. Blood and urine samples were collected at frequent intervals for 24 hr after the procainamide dose. There were no significant differences in the mean pharmacokinetic parameters of procainamide and NAPA after ranitidine coadministration compared to base line. However, individual changes did occur and regression analysis revealed a correlation between base-line procainamide renal clearance (CLR) and the change (delta) in CLR after ranitidine (r = 0.69, P less than .01). Subsequently, individuals were separated into Group I (n = 7) if they had a decrease or Group II (n = 6) if they had an increase in procainamide CLR after ranitidine. Mean +/- S.D. base-line procainamide CLR was 539 +/- 114 ml/min for Group I vs. 410 +/- 61 ml/min for Group II (P less than .01). During ranitidine coadministration, Group I had a 23% decrease in mean procainamide CLR (P less than .05), whereas Group II had a 21% increase (P less than .05). There were no significant differences in the metabolic clearance (CLM) of procainamide between the two groups at base line. However, Group I had a 45% increase (P less than .01) whereas Group II had a 41% decrease (P less than .05) in mean procainamide CLM with concomitant ranitidine.(ABSTRACT TRUNCATED AT 250 WORDS)

The antihypertensive response to lisinopril: the effect of age in a predominantly black population.

After a 2-4 week no-treatment period, 24 patients (12 young, age 29-45 yr.; 12 elderly, age 65-81 yr.; 20 black, 4 white) with an untreated sitting diastolic blood pressure between 91-120 mm Hg received the nonsulfhydryl angiotensin converting enzyme inhibitor, lisinopril for three weeks in a singleblind, parallel group comparison. Patients who did not achieve goal blood pressure with the initial low-dose (10 mg/day) were treated with a high-dose regimen (40 mg/day) for three weeks. In those who remained incompletely responsive, hydrochlorothiazide 25 mg/day was added for four weeks in an attempt to normalize blood pressure (less than or equal to 90 mm Hg). Low-dose lisinopril monotherapy produced comparable reductions in the mean systolic and diastolic blood pressures (approximately -15/-8 mm Hg in both younger and older patients). Increasing the dose produced a slightly greater fall in mean blood pressures which normalized the blood pressure in five of six elderly patients unresponsive to the lower dose; addition of hydrochlorothiazide normalized three of the five remaining subjects from both groups who were unresponsive to high dose lisinopril. Lisinopril administration resulted in a rise in plasma renin activity and a fall in plasma aldosterone concentrations which were similar in both groups and which returned over time toward the baseline. The drug was well tolerated, producing one episode of symptomatic hypotension following the addition of hydrochlorothiazide to lisinopril monotherapy. Lisinopril alone or in combination with hydrochlorothiazide produces favorable antihypertensive effects in both younger and older predominantly black, low-renin patients with essential hypertension.

Allergic reaction to antipyrine, a marker of hepatic enzyme activity.

Antipyrine is a pyrazole derivative used extensively as a marker for hepatic drug metabolizing enzyme activity. A subject participating in a clinical trial employing antipyrine experienced an acute allergic reaction to the drug which was characterized by diaphoresis, flushing, swelling of the throat, difficulty in breathing, vomiting, swelling of the upper lip, and a diffuse urticarial rash. Intravenous administration of diphenhydramine markedly improved the symptomatology. Clinical investigators as well as study participants should be alerted to the potential for antipyrine to cause an acute allergic reaction.

Antihypertensive response to ketanserin: influence of race and weight.

The antihypertensive effects of the 5-HT2 receptor antagonist ketanserin were evaluated in 16 patients with uncomplicated essential hypertension. Following a three week single-blind placebo treatment period, patients were randomized to receive in a double-blind manner oral ketanserin 20 mg or 40 mg twice a day for 10 weeks. In the racially mixed patient population, mean (+/- SD) seated blood pressure 12 hours after the last dose of placebo was 161 +/- 11/99 +/- 9 mm Hg and 155 +/- 19/98 +/- 10 mm Hg after ketanserin (P greater than .05). Ketanserin 20 mg twice a day did not lower blood pressure significantly. In contrast, 40 mg twice a day significantly decreased systolic blood pressure (P less than .02), and lowered diastolic blood pressure (P = .06). White patients (N = 7) showed a significant decrease in blood pressure (BP) with ketanserin treatment (158 +/- 5/98 +/- 8 vs. 147 +/- 13/92 +/- 6 mm Hg, P less than .05) while black patients (N = 9) did not (165 +/- 13/100 +/- 9 vs. 161 +/- 21/102 +/- 10 mm Hg, P greater than .05). For black patients only, significant correlations were observed between body weight and the change in diastolic BP (r = -.86, P less than .005). The racial difference in response to ketanserin could not be attributed to differences between the two groups in age, sex, body weight, pretreatment blood pressure or ketanserin dose. The nature of the racial difference in the chronic antihypertensive response to ketanserin warrants further evaluation.

Effects of gender, posture, and age on gastric residence time of an indigestible solid: pharmaceutical considerations.

We have recently reported the effect of varying food composition on the gastric residence time (GRT) of an indigestible solid, the Heidelberg capsule (HC). The purpose of the present evaluation was to evaluate the reproducibility and the effect of gender, posture, and age on the GRT of the HC. The reproducibility in measurement of the GRT of the Heidelberg capsule was evaluated in two trials separated by 1 week. Mean GRT values obtained in nine healthy men on day 1 were not statistically different from those on day 8 (3.5 +/- 0.6 vs 3.5 +/- 0.7 hr, P greater than 0.05). To evaluate the influence of gender on the GRT of the HC, 12 healthy male volunteers and 12 age (+/- 3 years)- and race-matched female counterparts entered into a randomized study. Each subject was served a standardized 500-kcal breakfast 30 min prior to oral ingestion of the HC. The mean (+/- SD) ambulatory GRT in the males was significantly faster than in the females (3.4 +/- 0.6 vs 4.6 +/- 1.2 hr, P less than 0.01). Influence of posture on the GRT of HC was examined in the same 12 men in a two-way, randomized, crossover study. The mean GRT for volunteers in the supine state was not statistically different from that in the upright, ambulatory state (3.4 +/- 0.8 vs 3.5 +/- 0.7 hr, P greater than 0.05). The effect of age on the GRT of the HC was evaluated in 12 healthy elderly males (greater than 65 years) with no prior gastrointestinal complications.(ABSTRACT TRUNCATED AT 250 WORDS)