Steady-state pharmacokinetics of diltiazem and hydrochlorothiazide administered alone and in combination.

Diltiazem and hydrochlorothiazide are widely used to treat cardiovascular disease, often in combination. The purpose of this investigation was to determine whether a drug-drug pharmacokinetic interaction exists between diltiazem and hydrochlorothiazide. In a randomized, crossover, open study, multiple doses of diltiazem (60 mg four times daily for 21 doses) and hydrochlorothiazide (25 mg twice daily for 11 doses) were administered alone and in combination on three separate occasions to 20 healthy male volunteers. Trough and serial blood samples were collected and plasma was assayed for diltiazem, hydrochlorothiazide, and diltiazem metabolites (desacetyldiltiazem and N-desmethyldiltiazem) using HPLC. Total urine was also collected and quantified for hydrochlorothiazide. Coadministered hydrochlorothiazide did not significantly (p > 0.05) alter diltiazem (alone versus combination) steady-state maximum plasma concentration (Css(max); 145 versus 158 ng mL(-1), respectively), time to maximum plasma concentration (t(max); 3.0 versus 2.8 h, respectively); area under the plasma concentration-time curve (AUCss; 688 versus 771 ng x h mL(-1)), oral clearance (Cl(oral); 96.2 versus 88.0 L h(-1)), or elimination half-life (t(1/2); 5.2 versus 5.2 h). Similarly, administration of diltiazem did not significantly (p > 0.05) influence hydrochlorothiazide (alone versus combination) Css(max) (221 versus 288 ng mL(-1)), t(max) (1.8 versus 2.0 h), AUCss (1194 versus 1247 ng x h mL(-1)), Cl(oral) (22.4 versus 21.2 L h(-1)); t(1/2) (9.8 versus 9.6 h), or renal Cl (15.5 versus 15.2 L h(-1)). In conclusion, a clinically significant pharmacokinetic interaction between diltiazem and hydrochlorothiazide does not exist.

Percutaneous absorption of ketoprofen from different anatomical sites in man.

PURPOSE: The purpose of this study was to investigate the percutaneous absorption of ketoprofen applied topically to different anatomical sites on the body. METHODS: The study design was a randomized, four-way crossover in 24 healthy male subjects. One gram of ketoprofen 3% gel (30 mg dose) was applied every six hours for 25 doses over a 100 cm2 of the back, arm, and knee. A 0.5 ml of ketoprofen solution (60 mg/ml) was applied to the back as a reference treatment. Plasma and urine samples were obtained for the assay of racemic ketoprofen and ketoprofen enantiomers (S and R), respectively. RESULTS: The relative bioavailabilities of ketoprofen gel were 0.90 +/- 0.50, 1.08 +/- 0.63, and 0.74 +/- 0.38 when applied to the back, arm, and knee, respectively. The plasma ketoprofen C(max) for gel applied to the back and arm are similar (p > 0.05) but C(max) was lower when applied to the knee (p < 0.05). The time to C(max) ranged from 2.7 to 4.0 hours and was similar for gel treatments on the back and arm, but no longer for the knee treatment. The fraction of dose excreted in urine as total S and R enantiomers ranged from 5.41 to 9.10%. CONCLUSIONS: The percutaneous absorption of ketoprofen was similar when applied to either the back or arm but was lower when applied to the knee.

Pharmacokinetics of 5-aminosalicylic acid from controlled-release capsules in man.

One gram single dose of Pentasa controlled-release capsules was administered to 24 healthy volunteers under fasting condition. Mean plasma 5-aminosalicylic acid (5-ASA) and acetyl 5-ASA concentrations peaked at 0.53 microgram.ml-1 and 1.33 micrograms.ml-1 from 3 to 4 hours following dosing, respectively. The half-lives of both compounds could not be determined as absorption of 5-ASA was continuous throughout the gastrointestinal tract. An average of 29.4% (CV: 27%) of the dose was excreted in the urine primarily as acetyl 5-ASA. Up to 91.1% of the dose was released from the capsules. Forty percent of the dose (CV: 40%) was eliminated in the feces, with 8.9% of the dose remained as formulation bounded 5-ASA, indicating that controlled-release capsules continue to release drug throughout the GI tract. 5-ASA contributed 46.7% of the salicylates eliminated in the feces and acetyl 5-ASA accounted for the balance. Controlled-release capsules produced three times more total salicylates and 10 times more total and free 5-ASA in the feces than did 5-ASA suspension. Thus, while lower systemic levels of salicylates were absorbed, greater therapeutic quantities of 5-ASA were available in the bowel.

Pharmacokinetics of diltiazem and propranolol when administered alone and in combination.

Multiple oral doses of diltiazem (DTZ) and propranolol (PPL, 60 mg every 8 h daily for 13 doses) were administered to 14 healthy volunteers alone and in combination on three separate occasions. Serial blood samples were collected up to 24 h after dose 13 on day 5 to determine possible pharmacokinetic interactions between the two drugs. When administered alone, DTZ concentration peaked at 161.4 ng ml-1 3 h following the final dose with an elimination half-life of 6.1 h. DTZ oral clearance was 65.1 l h-1. PPL did not affect DTZ oral clearance and half-life during the combination treatment. However, DTZ tmax was extended from 2.9 h to 3.5 h (p less than 0.05) and Cmax was 144.7 ng ml-1. Unlike the parent drug DTZ, desacetyldiltiazem (DAD) plasma profile was elevated during the combination treatment. DAD Cmax and AUC both increased approximately 20 per cent (p less than 0.05). PPL pharmacokinetics were altered as well. Oral clearance of PPL decreased from 80.4 l h-1 to 61.0 l h-1 while the half-life increased from 5.9 h to 8.0 h (p less than 0.05). PPL Cmax increased from 155.1 ng ml-1 to 167.5 ng ml-1.

Effect of food coadministration on 5-aminosalicylic acid oral suspension bioavailability.

Single doses of 1 gm 5-aminosalicylic acid (5-ASA) suspension was administered to 24 healthy volunteers during both fasting and fed conditions. For subjects in a fasting state, plasma 5-ASA and acetyl 5-ASA concentrations peaked rapidly 1 hour after dosing to 14.72 micrograms/ml and 11.4 micrograms/ml, respectively. The elimination half-life of 5-ASA was 51.9 minutes, whereas the acetyl 5-ASA half-life could not be determined. A mean of 78.3% of the dose was excreted in the urine, with 5-ASA accounting for 21.2% of the dose and acetyl 5-ASA accounting for the balance. Only 11.3% of the dose was eliminated in the feces, consisting mostly of acetyl 5-ASA. Food coadministration reduced 5-ASA and acetyl 5-ASA systemic relative bioavailability to 44% and 76%, respectively, compared with the fasting treatment. Urinary excretion of the salicylates was reduced to 46.8%, and fecal salicylate elimination increased almost 100%--to 24.2% of the total dose.

Near-fatal caffeine intoxication treated with peritoneal dialysis.

Caffeine is generally regarded as a safe drug, as evidenced by its wide availability in "over-the-counter" preparations and beverages. However, it is capable of producing a lethal outcome in cases of intoxication. The case of a two-year-old girl, who suffered major poisoning from caffeine, is presented. Her care, including the use of peritoneal dialysis, is discussed. Previous cases of caffeine intoxication meriting hospital care or resulting in death which have been reported in the English language medical literature are summarized. It is suggested that drug-drug interactions and the use of peritoneal dialysis and hemoperfusion be given particular consideration in such patients.

Plasma and saliva propafenone concentrations at steady state.

Twenty-four healthy male subjects were administered 300 mg of propafenone every 8 h for 6 d in each of two phases that were separated by 2 d. Plasma samples were collected during the approach to steady state for each phase, and plasma and saliva samples were collected frequently at steady state. Both plasma and saliva propafenone were assayed by a specific HPLC method. Two estimates of elimination half-life (t1/2), mean steady-state concentration (CPss), time to maximal concentration (tmax), and maximal concentration (CPmax) were estimated for each subject. Also mean steady-state saliva concentrations (CSss), time to maximal saliva concentration (tSmax), and maximal saliva concentrations (CSmax) were estimated. A large intersubject variance in both t1/2 and CPss were observed in the 24 subjects, with the t1/2 values ranging from 2.1 to 27.2 h and the CPss values from 0.3 to 3.03 microgram/mL. Each subject was quite consistent for the two phases, suggesting a relatively low intrasubject variance for propafenone kinetics. A histogram shows most subjects to have t1/2 values between 2 and 10 h, with diminishing numbers of subjects at greater t1/2 values rather than a bimodal distribution. Saliva concentrations ranged from 12 to 72% of the corresponding plasma concentrations, being 24.7 +/- 11.1% of the simultaneously collected plasma sample overall (mean +/- SD). a significant (p less than 0.001) positive correlation exists between CPss and CSss.

Food increases the bioavailability of propafenone.

The effect of food intake on the bioavailability of propafenone, a new antiarrhythmic agent, was evaluated by comparing its kinetics in 24 healthy volunteers in a fasted state and after a standard breakfast. With food, the maximum plasma drug concentration was reached earlier and was significantly increased. When data from 'slow' metabolizers were excluded, there was an average increase of 147% in the area under the concentration-time curve (AUCo) following the standard breakfast. There was a significant correlation (r = 0.946) between [(AUCo fed - AUCo fasted)/AUCo fasted] and propafenone intrinsic clearance in the fasted state. Food intake, however, does not appear to affect the bioavailability of propafenone in 'slow' metabolizers. Patients should be advised to take propafenone in a constant relationship to food to assure consistent bioavailability.

Pharmacokinetics of dothiepin in humans: a single dose dose-proportionality study.

Dothiepin hydrochloride (N,N-dimethyldibenzo[b,e]thiepin-delta 11(6 H), gamma-propylamine hydrochloride) is a tricyclic antidepressant which is structurally similar to amitriptyline. Twenty-seven healthy men received three single oral doses of 50-, 100-, and 150-mg dothiepin hydrochloride capsules in a three-way randomized, crossover dose-proportionality study. Plasma concentration-time profiles of dothiepin (1) were described by both one- and two-compartment models with first-order absorption. The total intrinsic clearance of dothiepin decreased from 165.5 to 121.1 L/h as the dose was increased from 50 to 150 mg, but there was no significant effect on the terminal half-life (approximately 20 h). Plasma concentration-time profiles of the three major metabolites of dothiepin, the S-oxide derivative of dothiepin, N,N-dimethyl[b,e]thiepin-delta 11(6 H), gamma-propylamine 5-oxide (2), the demethyl derivative, N-methyldibenzo[b,e]thiepin-delta 11(6 H), gamma-propylamine (3) and the demethyl S-oxide derivative N-methyldibenzo[b,e]thiepin-delta 11(6 H), gamma-propylamine 5-oxide (4), were described by a one-compartment model with apparent first-order formation. The AUC infinity values of the S-oxide 2 and the demethyl S-oxide 4 increased proportionally with dose. The dose proportionality of the demethyl metabolite 3 may not be ascertained from the data in this study. The corresponding half-lives of the three metabolites, which are dose independent, were approximately 24, 28, and 40 h, respectively.

Transport of choline out of the cranial cerebrospinal fluid spaces of the rabbit.

The role which carrier-mediated transport and passive diffusion play in the clearance of quaternary ammonium compounds from cerebrospinal fluid was evaluated by ventriculocisternal perfusion in rabbits by using [14C]choline as the primary test compound. Choline was transported out of cerebrospinal fluid by two processes: a saturable, carrier-mediated process with a Tmax of 70.5 ng/min and Kt of 2.2 microgram/min; and, a passive nonsaturable process with a cerebrospinal fluid perfusate clearance of 11.5 microliter/min. N1-methylnicotinamide depressed the clearance of choline as well as that of hexamethonium, suggesting that these cations share a common transport process. Ouabain reduced the clearance of choline and hexamethonium. Passage of choline into brain occurred by passive diffusion.

Bioavailability of theophylline following a rectally administered concentrated aminophylline solution.

A two-way complete crossover bioavailability study of solutions of theophylline given orally or rectally in 16 healthy subjects was conducted. Blood samples were obtained prior to dosing and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2,5, 3, 3,5, 4, 4.5, 5, 6, 7, 8, 10, 12, and 24 hr. Plasma theophylline was determined by high-pressure liquid chromatography. In the fasting subjects solutions given orally were absorbed faster (0.95 versus 1.95 hr to peak), reaching a higher peak concentration (7.26 versus 4.87 microgram/ml) than the solutions given rectally. Depending on the method of computation, solutions given rectally were estimated to be 86% to 87% as biovailable as the solutions given orally, with 75% of the subjects having 80% or greater relative bioavailability.

Binding of organic compounds to rat liver and lung.

The binding of various radioisotopically labeled organic compounds to rat liver and lung was investigated in vitro. Pieces of rat lung and slices of rat liver were incubated at 37 degrees C under a nitrogen atmosphere in a modified Krebs-Ringer phosphate solution (pH 7.4) CONTAININg the compound to be studied. Of the neutral compounds investigated, digitoxin, digoxin and dexamethasone were highly bound to both liver and lung tissue, whereas the degree of binding of amitrole, erythritol, and ouabain was 20% or less. The weak acids which were bound to the greatest extent in both liver and lung were phenobarbital, pentobarbital, and diphenylhydantoin. Barbital was poorly bound, and there was no evidence for the binding of 5,5-dimethyloxazolidine-2,4-dione or p-aminohippuric acid in either tissue. Binding of the cardiac glycosides and the barbiturates directly paralleled their lipid solubilities. The degree of binding of neutral compounds and weak acids to lung and liver tissue did not vary greatly with concentration, even though broad concentration ranges were studied. This was also true of the weak base morphine. On the other hand, the binding to liver and lung of the organic bases nicotine, pilocarpine, d-amphetamine, lidocaine, erythromycin, and chloroquine, did vary with concentration. The quaternary ammonium compound decamethonium was bound only to liver, and this binding also varied with concentration. Two additional quaternary ammonium compounds, tetraethylammonium and N1-methylnicotinamide, were not significantly bound to either tissue. Comparisons on the basis of equal content of solids revealed that the binding of diverse organic compounds in liver is greater than or equal to that in lung.