Gastrointestinal absorption as a function of age: xylose absorption in healthy adults.

Xylose oral absorption was examined in 24 healthy male subjects ranging in age from 32 to 85 years. Absorption was evaluated from xylose plasma concentration-time data after administration of a 25 gm po or a 5 gm iv dose. There was no relationship between various estimates of the rate of absorption and age. The absolute oral bioavailability or the extent of xylose absorption showed no relationship to age in our population. In contrast with previous suggestions, xylose absorption does not decline with age. General statements of decreased gastrointestinal absorption efficiency as a function of age may not be correct.

Digoxin bioavailability during quinidine administration.

Digoxin serum concentration rises in the presence of quinidine. To determine whether quinidine alters digoxin bioavailability, six subjects received 1.0 mg of digoxin intravenously alone and by mouth on alternate weeks during steady-state oral quinidine administration. The area under the digoxin concentration:time curves (AUC) and the amount of digoxin excreted in the urine (Xxu) were determined for the 96 hr after each of the four experiments. Values for digoxin bioavailability relative to the corresponding intravenous study in the absence and presence of quinidine were (+/- S.D.) 73.5 +/- 8.6% and 79.5 +/- 22.6% (P greater than 0.05) for serum and 69.8 +/- 6.8% and 70.2 +/- 10.5% (P greater than 0.05) for urine. There was no difference in the steady-state quinidine serum concentration during the 4 days after intravenous and oral digoxin. We conclude that quinidine does not alter digoxin bioavailability and therefore that altered absorption does not explain the rise in digoxin serum concentration in the presence of quinidine.

Xylose disposition in humans as a function of age.

D-xylose disposition was examined in 24 healthy men between 32 and 85 years of age. Xylose was administered as a 5 gm iv infusion and as a 25 gm po solution. Serum xylose concentrations and urinary excretion of intact xylose were determined. There were statistically significant inverse relationships with age for each of the following parameters after intravenous infusion: elimination rate constant (r2 = 0.71); systemic clearance (r2 = 0.66); renal clearance (r2 = 0.66); and nonrenal clearance (r2 = 0.35). Similar inverse relationships were found after oral dosing for the elimination rate constant (r2 = 0.69) and renal clearance (r2 = 0.54). There was no significant age relationship for the apparent volume of distribution or the steady-state volume of distribution. The percentage of the oral and intravenous dose recovered in urine up to 5 hours after dosing was significantly and inversely correlated with age. The implications of the latter finding are discussed with regard to the interpretation of the xylose tolerance test used to assess gastrointestinal absorptive capacity.

Disposition kinetics of two oral forms of quinidine.

There are relatively few studies on the disposition properties of quinidine. We have studied in 10 normal subjects conventional quinidine sulfate and a slow-release quinidine bisulfate. Single and repetitive doses were given; blood and urine concentrations were measured by the method of Cramer and Isaakson. After a single dose of two tablets of quinidine sulfate (400 mg), the average peak concentration was 2.13 +/-0.22 mug/ml (+/-SEM); following two tablets of the slow-release form, the average peak concentration was 1.17 +/-0.12 mug/ml. T-max was approximately 2 hr with quinidine sulfate and 4 hr with quinidine bisulfate. One fourth of both forms of the drug was recovered in the urine. Total body clearance was 0.36 L/kg-hr and renal clearance was 117 +/-22ml/min for both. With multiple dosing the serum quinidine concentration was higher than these predicted from the results of the single-dose study. Based on the mean estimates of quinidine half-life of 6 hr, a rapid method for achieving steady-state levels of quinidine would be to give an initial dose twice that of the maintenance dose. With the slow-release product if an equivalent dose was given every 12 hr, the mean steady-state quinidine serum concentration would be approximately the same.

Kinetic evaluation of the propranolol-quinidine combination.

The kinetics of quinidine and propranolol, administered singly and in combination, were evaluated in 5 healthy subjects. The orally administered doses resulted in plasma concentrations within the therapeutic range. For each drug the average steady-state plasma concentration, maximal plasma concentration, and time of maximum plasma concentration were not altered by the presence of the other drugs. This study shows no kinetic interaction between quinidine and propranolol in normal subjects.

Disposition kinetics of moclobemide, a monoamine oxidase-A enzyme inhibitor: single and multiple dosing in normal subjects.

The absorption and disposition kinetics of moclobemide (Ro 11-1163), a new reversible and preferential monoamine oxidase-A enzyme inhibitor, were examined in 12 normal male subjects. An intravenous infusion was administered before and after a 15-day multiple oral dosing regimen (100 mg t.i.d.). Plasma concentration-time data were obtained after each intravenous infusion, after the first oral dose, during two dosing intervals at steady state, and before the second daily dose on several days. The disposition values (percent coefficient of variation in parentheses) after the first and second intravenous infusions, respectively, were: clearance, 39.4 (15%) and 29.1 (12%) L/hr; elimination half-life, 1.60 (15%) and 2.00 (18%) hours; and volume of distribution at steady state, 84.3 (11%) and 80.7 (15%) L. The absolute oral bioavailability increased from 0.56 after the first oral dose to 0.86 and 0.90 after the first and second weeks of administration, respectively. The reduced metabolic, presumably hepatic, clearance may be the result of self-inhibition or metabolite inhibition of moclobemide clearance.

Assessment of beta blockade with propranolol.

Each of seven subjects received on a weekly basis placebo or 10, 20, 40, 80, or 160 mg propranolol orally four times daily. The effect of propranolol on the resting heart rate and the heart rate responses to the Valsalva maneuver, tilt, isoproterenol, and maximal exercise were measured. Coefficients of determination were calculated from the individual dose-response curves. The results indicate that the resting heart rate and the tachycardiac response to the Valsalva maneuver and tilt cannot be used to estimate beta blockade. Propranolol concentrations correlated well (mean r2 = 0.80) with the isoproterenol dose ration minus one, but isoproterenon challenges appear clinically inapplicable. Reduction in maximal exercise tachycardia correlated best with propranolol concentrations (mean r2 = 0.89) but, to the extent that exercise could not be performed, there was no reliable way of clinically documenting beta blockade and only the serum concentration of propranolol was available as an indicator of appropriate therapy.

Pharmacokinetics of the aldose reductase inhibitor tolrestat: studies in healthy young and elderly male and female subjects and in subjects with diabetes.

Tolrestat is an aldose reductase inhibitor undergoing clinical trials in diabetic subjects that may reduce the severity of chronic tissue damage associated with hyperglycemia. These studies were conducted to evaluate the pharmacokinetics of tolrestat in healthy young and elderly male and female subjects and in young and elderly subjects with diabetes. The drug was administered in a multiple-dose regimen, and steady-state parameters were obtained. There were no important gender-related differences, but mean values for apparent oral clearance, renal clearance, and corresponding unbound parameters were significantly lower for the elderly healthy subjects than for the young healthy subjects. The drug is highly bound to plasma proteins, and the unbound fraction (0.75%) did not differ among the subjects. The results from young and elderly diabetic subjects suggest that diabetes per se has no influence on tolrestat disposition but that there is an age-related reduction in apparent oral clearance (30 versus 18 ml/hr/kg) and a corresponding increase in the minimum steady-state plasma concentration (1.2 versus 1.9 micrograms/ml). These data indicate a possible need to reduce the dose of tolrestat in elderly subjects, assuming the same concentration-response relationship.

Cimetidine alters the disposition kinetics of the monoamine oxidase-A inhibitor moclobemide.

The influence of cimetidine on the absorption and disposition of moclobemide was examined in eight healthy male subjects. A single 100 mg intravenous and 100 mg oral dose of moclobemide was administered before and after 2 weeks of cimetidine administration (200 mg five times a day). The data on intravenous administration indicated that cimetidine produced a statistically significant alteration in the following disposition parameters (mean values for control versus cimetidine): systemic clearance, 46.6 versus 28.3 L/hr; mean residence time, 2.1 versus 3.2 hours; elimination half-life, 1.6 versus 2.3 hours. There was no significant difference in the steady-state volume of distribution. The absolute oral bioavailability of moclobemide increased significantly after cimetidine administration (54% versus 68%), as did the maximum plasma concentration after a single oral dose (575 versus 787 ng/ml). There were no differences in the mean absorption time or time to achieve maximum concentration. The values of systemic and apparent oral clearances of moclobemide after cimetidine administration were directly related to the corresponding control values before cimetidine. In contrast, the percentage change in clearance was essentially independent of the corresponding initial control clearance value.

Clinical pharmacokinetics of the monoamine oxidase-A inhibitor moclobemide.

There has been a resurgence of interest in the use of monoamine oxidase (MAO) enzyme inhibitors for the treatment of depression. Unlike the first-generation MAO inhibitors, the current drugs are readily reversible in their action, resulting in far less concern about interactions with certain foods and drugs which could lead to serious pressor effects. Furthermore, the current drugs are far more selective in their actions as a result of the ability to affect either the MAO-A or the MAO-B isoenzyme. Moclobemide is an example of a reversible MAO-A inhibitor which has been extensively studied and whose pharmacokinetic, clinical pharmacological and toxicological profiles have been thoroughly defined. Moclobemide has a short disposition half-life and intermediate values for systemic clearance and volume of distribution; half-life increases somewhat with dose. The drug is completely metabolised by the liver. Moclobemide is rapidly and completely absorbed following oral administration in a variety of dosages and forms. The drug has a high intrinsic (apparent oral) clearance which results in a substantial hepatic first-pass effect and, while there is marked interindividual variation, differences within an individual are small. A time- and dose-dependence is observed with multiple oral administration: clearance decreases with administration during the first week and thereafter remains constant. The exact mechanism of this effect is not known, but it may reflect inhibition of elimination by metabolites (the kinetics may always be described as being first-order). Moclobemide disposition is not affected by renal disease, nor is there substantial alteration with advanced age. Liver disease causes a dramatic reduction in clearance; dosage must be adjusted for patients with liver disease. There is minimal transfer of the drug into breast milk, such that breast-feeding neonates are exposed to only a very small dose of the drug. Moclobemide administration results in a minimal interaction with exogenous amines (e.g. tyramine and pressor amine drugs); the so-called 'cheese effect' is therefore of little concern. As a result, the drug has an excellent tolerability profile both within the therapeutic dose range and in overdose (no deaths have been attributed to moclobemide intoxication per se). Cimetidine inhibits the elimination of moclobemide. Moclobemide appears to affect several isoenzymes of the cytochrome P450 (CYP) system (CYP2C19, CYP2D6 and CYP1A2). The adverse events profile of moclobemide indicates only mild and transient effects at a relatively low rate of occurrence.

Efficacy, plasma concentrations and adverse effects of a new sustained release procainamide preparation.

To assess the efficacy, plasma drug concentrations and adverse effects of a new sustained release preparation of procainamide, 33 patients with heart disease were studied in an acute dose-ranging protocol and a chronic treatment protocol. Patients initially received a daily dose of 3 g of sustained release procainamide; this dose was increased by 1.5 g daily until ventricular premature depolarizations were suppressed by 75 percent or more, adverse drug effects occurred or a total daily dose of 7.5 g of sustained-release procainamide was reached. Twenty-five patients (76 percent) had at least a 75 percent reduction (range 75 to 100percent [mean +/- standard deviation 91 +/- 8.2]) in ventricular permature depolarization frequency at a dosage of 4.8 +/- 1.46 g/day (range 3.0 to 7.5). Despite the 8 hour dosing interval, the variation between maximal and minimal plasma procainamide and N-acetylprocainamide concentrations under steady state conditions was very small. Mean maximal procainamide and N-acetylprocainamide plasma concentrations were 10.4 +/- 6.02 and 12.0 +/- 7.40 micrograms/ml, respectively. The respective mean minimal concentrations were 6.8 +/- 4.50 and 8.7 +/- 5.99 micrograms/ml. In nine patients (27 percent) treatment with sustained release procainamide resulted in conversion of the antinuclear antibody test from negative to positive. Adverse drug effects occurred in 17 (52 percent) of the subjects. In general, adverse effects were minor and abated within 24 hours after administration of the drug was stopped. One patient had the procainamide-induced systemic lupus erythematosus-like syndrome.

Pharmacokinetics in the elderly.

Animals undergo substantial changes in many physiologic and biochemical functions as a natural consequence of aging. In the absence of disease or other pathologic conditions, these changes occur in a gradual manner with time (generally expressed as a fractional or percentage change in that function per year or decade). Furthermore, for any given function and at any given chronologic age, there is large variation in that function among individuals. Given the increase in life expectancy, the substantial increase in the number of elderly (and aged elderly) in the population, and the escalating costs of health care, there is great interest in learning more about the risks associated with aging as a result of toxic exposure. Are the elderly at greater risk than younger adults to the toxic effects of drugs and environmental exposure? Is the elderly population an inherently more sensitive one?

The influence of age on salicylate pharmacokinetics in humans.

The pharmacokinetics of salicylate after a single oral solution dose of 600 mg of sodium salicylate were investigated in 22 male subjects. Subjects were healthy nonsmokers and were not taking any regular medication. The plasma concentration and urinary excretion of salicylic acid and its metabolite, salicyluric acid, as well as the urinary excretion of salicyl glucuronides were determined. Urinary recovery essentially accounted for the administered dose and was not influenced by age, nor was the apparent oral clearance of salicylic acid. Assuming no presystemic elimination, it could be concluded that systemic availability is unaffected by age. An increase in the apparent volume of distribution, Varea, and a decrease in the maximum plasma salicylic acid concentration with age were observed. Renal clearance of salicyluric acid decreased significantly with age and was found to correlate significantly with creatinine clearance. The authors conclude that age does not have a major influence on salicylate disposition in healthy adult men.

The influence of cimetidine on the disposition kinetics of the antidepressant venlafaxine.

The influence of cimetidine on the disposition pharmacokinetics of the antidepressant drug, venlafaxine, and its active metabolite, O-desmethylvenlafaxine, was examined in 18 healthy young men and women. The steady-state pharmacokinetic profiles of venlafaxine and O-desmethylvenlafaxine were evaluated during a 24-hour period after 5 days of treatment with venlafaxine (50 mg three times a day) and during a second 24-hour period after 5 days of combination treatment with venlafaxine (50 mg three times a day) and cimetidine (800 mg once a day). The apparent oral clearance of venlafaxine decreased significantly in the presence of cimetidine and the average steady-state plasma concentration of venlafaxine increased significantly in the presence of cimetidine, but there were no changes in the corresponding concentrations of the active metabolite. However, O-desmethylvenlafaxine exhibits pharmacologic activity that is approximately equimolar to that of venlafaxine, and the sum of venlafaxine plus O-desmethylvenlafaxine plasma concentrations was increased by an average of only 13%. Therefore, the effect of cimetidine coadministration is not expected to result in clinically important alterations in the response to venlafaxine in patients with depression. This may not be true, however, for patients with compromised hepatic metabolic function.

Disposition kinetics of moclobemide, a new MAO-A inhibitor, in subjects with impaired renal function.

A single intravenous and oral dose of moclobemide (Ro 11-1163) was administered to 13 subjects with varying degrees of renal impairment (creatinine clearances ranging from 0 to 40 mL/min). The resulting disposition and absorption parameters of moclobemide were more variable than but, with the exception of mean absorption time, were not significantly different from values obtained in another study conducted in 12 normal healthy subjects. There were no relationships between any of the disposition parameters and renal function as measured by creatinine clearance. The disposition of two metabolites of moclobemide were partially characterized from plasma data. One of these (Ro 12-8095) appears to be formation rate-limited and, from available data, behaves in a manner similar to what has been observed in normals. The other metabolite (Ro 12-5637) has a long apparent disposition half-life and is present in greater concentrations in the renally impaired compared to the normal subjects. The latter observation may reflect reduced elimination clearance in the renally impaired subjects. Based upon the results of this study there does not appear to be any need to alter the normal dosing regimen of moclobemide in subjects with renal impairment in order to achieve drug concentrations similar to those in healthy subjects.

Moricizine bioavailability via simultaneous, dual, stable isotope administration: bioequivalence implications.

The relative bioavailability of a 200 mg film-coated tablet of [12C]moricizine.HCl in comparison to a 200 mg [13C6]moricizine.HCl oral solution was determined after simultaneous administration to 8 young healthy male subjects. Concentrations of [12C]moricizine.HCl and [13C6]moricizine.HCl were determined by thermospray liquid chromatography-mass spectrometry (LC-MS) using [2H11]moricizine.HCl as the internal standard. The mean absorption and disposition parameters of the tablet versus the solution were the following (%CV): maximum concentration, 0.83 (39%) versus 0.79 (39%) microgram/mL; time of maximum concentration, 0.81 (40%) versus 0.65 (28%) hours; area under the concentration-time curve (AUC), 1.58 (39%) versus 1.49 (37%) micrograms.h/mL; apparent oral clearance, 150.7 (52%) versus 158.1 (50%) L/h; and t1/2, 1.9 (42%) versus 1.9 (42%) hours. The AUC for the tablet averaged 106% of the solution, which likely reflects a greater first-pass effect with the oral solution. Partitioning sources of variation confirmed the low (< 6%) intrasubject coefficient of variation (cv epsilon) afforded via the single-period, dual-isotope design. In contrast, a previous study using the conventional two-period crossover design determined the cv epsilon about moricizine metrics to be in excess of 30%, resulting in classification of this drug as having highly variable absorption. The results of this study further illustrate the benefits of dual, stable isotopes to assess bioavailability and bioequivalence. This paradigm results in a reduction in experimental time and subject inconvenience and lower costs in comparison with the standard crossover study. Perhaps most important is the improved statistical power for the evaluation of bioavailability or bioequivalence in the absence of period and sequence effects that confound the assessment of intrasubject variation in the standard crossover design.

Cimetidine disposition in patients undergoing continuous ambulatory peritoneal dialysis.

Cimetidine disposition was determined in six patients undergoing continuous ambulatory peritoneal dialysis to ascertain the need for modification of conventional dosing regimens. Blood, dialysis fluid, and urine were collected for 48 hours after administration of a single intravenous dose of cimetidine. The following values were obtained: elimination half-life, 4.3 hours; systemic or total body clearance, 191 +/- 55 ml/min; and dialysis clearance, 4.2 +/- 3.1 ml/min. Approximately 2% of a cimetidine dose is removed by dialysis, indicating that there is no need to adjust the conventional renal failure dosing regimen in patients undergoing continuous ambulatory peritoneal dialysis.

Allopurinol kinetics and bioavailability. Intravenous, oral and rectal administration.

Six normal, healthy adult males received a single dose of allopurinol intravenously, orally in the form of a commercial tablet, and rectally in the form of an extemperaneously prepared suppository (either in a cocoa butter or in polyethylene glycol base). Plasma allopurinol and oxipurinol concentrations were measured over a period of at least 60 h. The following mean (+/- SD) values were obtained from the intravenous allopurinol experiment: clearance, 9.62 +/- 3.49 ml . kg-1 . min-1; Vd, 1.61 +/- 0.74 l/kg; t1/2, 1.62 h. Oxipurinol had a mean t1/2 of 16.90 h. The absolute systemic bioavailability of the oral tablet was 67% +/- 23%, while the allopurinol rectal suppositories produced no measurable plasma concentrations of allopurinol or oxipurinol in any of the subjects. Current use of rectal dosage forms as an adjunct in cancer chemotherapy should therefore be re-examined.

Quantitation of xylose from plasma and urine by capillary column gas chromatography.

A specific and sensitive assay for quantitation of xylose from plasma and urine has been developed. Following a clean-up procedure, plasma (0.1 ml) or urine (0.2 ml) samples are concentrated and undergo two sequential derivatization steps. A methyloxime derivative is formed initially, followed by trimethylsilylation of all hydroxyl groups. The derivatized samples are quantitated by capillary column gas chromatography using flame ionization detection. Xylose and the internal standard (2-deoxy-D-ribose) have retention times of 6.5 and 5.2 min, respectively. Other monosaccharides (e.g. ribose, arabinose) do not interfere with the assay. Standard curves are linear and reproducible over a concentration range of 10-200 mg/l for plasma and 100-2000 mg/l for urine. The within-day and day-to-day percentage coefficients of variation were less than 5 and 9%, respectively, for plasma and urine.

Simple apparatus for serial blood sampling in rodents permitting simultaneous measurement of locomotor activity as illustrated with cocaine.

A simple device has been developed for serial venous blood sampling which permits the simultaneous measurement of locomotor activity in the freely moving rat. The device can be easily constructed from routine laboratory material and it does not interfere with the light beams used to measure locomotor activity. The device, in conjunction with an activity cage, has been applied to the combined pharmacokinetic and pharmacodynamic modeling of cocaine. The relationship between the locomotor activity following a single short iv infusion of cocaine (5 mg/kg) and cocaine plasma concentrations can be adequately described by the Sigmoid-E(max) model. Further, the relationship between activity and time can be described by the same model coupled with an effect compartment. These results suggest the applicability of the device in facilitating pharmacokinetic/pharmacodynamic modeling of drugs that affect locomotor activity.