The effects of acetaminophen on pharmacokinetics and pharmacodynamics of warfarin.

The oral anticoagulant warfarin is clinically administered as a racemic mixture of two enantiomers, (R) and (S). Many relevant drug interactions with warfarin have been attributed to the specific metabolic inhibition of the elimination of the more pharmacologically active (S)-enantiomer. To investigate reports that acetaminophen can potentiate the anticoagulant effect of warfarin, 20 healthy male volunteers were each given single oral 20 mg doses of racemic warfarin on three separate occasions: (1) alone, (2) after 1 day of acetaminophen (4 g/d), and (3) after 2 weeks of acetaminophen (4 g/d). The urinary excretion pattern of acetaminophen and its metabolites was not significantly altered over its course of administration. The (R)- and (S)-enantiomers of warfarin exhibited significantly different pharmacokinetic properties. However, acetaminophen did not alter the disposition of either (R)- or (S)-warfarin. All subjects exhibited a pharmacodynamic response to racemic warfarin. The response was not significantly altered in the presence of acute or chronic acetaminophen dosing, as assessed by prothrombin time and factor VII concentrations.

Serum concentrations of salicylic acid following topically applied salicylate derivatives.

OBJECTIVE: To compare the rate and extent of systemic salicylate absorption following single and multiple applications of two topically applied analgesics, one containing methyl salicylate and the other containing trolamine salicylate. DESIGN: Two-period, two-treatment, randomized, crossover, multiple-dose study in healthy men and women volunteers. PARTICIPANTS: Six men and six women volunteers, 21-44 years of age. INTERVENTIONS: Subjects applied 5 g of an ointment containing 12.5% methyl salicylate twice daily for 4 days (8 doses) or a cream containing trolamine 10% twice daily for two doses, to a 10-cm2 area on the thigh. Treatment order and leg (right or left) were assigned randomly. Subjects were crossed over to the alternate treatment on the other leg after a minimum washout period of 7 days. MAIN OUTCOME MEASURES: The total amount of salicylate recovered in the urine during two dosing intervals (24 hours) on each study day, relative to the applied dose, was used to calculate the bioavailability of each product. Mean standard pharmacokinetic parameters including area under the curve, maximum concentration (Cmax), time to maximum concentration, and minimum concentrations at steady-state were determined from serum concentrations. Serum concentrations were fit to three pharmacokinetic models and the suitability of each model was evaluated. Estimates of absorption rate constant, clearance, volume, and fraction absorbed on day 1 were estimated by using the best-fitting model. RESULTS: Salicylic acid could not be detected in serum after trolamine application. However, concentrations between 0.31 and 0.91 mg/L were detected within 1 hour of the first application of methyl salicylate and Cmax between 2 and 6 mg/L were observed following the seventh application on day 4. Both the extent and rate of absorption changed after the first 24 hours. The absorption rate constant increased significantly from the first to the seventh dose (first dose absorption rate constant: 0.16 h-1, seventh dose: 0.28 h-1; p < 0.035). Urinary recovery of total salicylate (salicylic acid and principal metabolites of salicylic acid) during the first 24 hours of the methyl salicylate phase averaged 175.2 mg, exceeding the 6.9 mg (p < 0.05) recovered during the trolamine phase. The recovery of salicylate in the urine in the first 24 hours after application of methyl salicylate was significantly greater than the 1.4% recovered after application of trolamine (p < 0.05). Furthermore, the fraction of methyl salicylate recovered in the urine increased significantly from 15.5% on day 1 to approximately 22% on the second, third, and fourth days. CONCLUSIONS: A considerable amount of salicylic acid may be absorbed through the skin after topical application of methyl salicylate products and this may increase with multiple applications. Caution is warranted in patients for whom systemic salicylate may be hazardous or problematic.

Abnormal serum transaminases following therapeutic doses of acetaminophen in the absence of known risk factors.

J.M., a healthy, 25-year-old male, volunteered for a study involving warfarin and acetaminophen. Acetaminophen 1 g four times a day was started for 21 days. Liver function tests taken at regular intervals for the first 12 days were unremarkable. On day 18, however, aspartate aminotransferase (AST) was 527 IU/liter and alanine aminotransferase (ALT) was 166 IU/liter. Acetaminophen was discontinued and serum transaminase levels returned to baseline levels two weeks later (AST = 26, ALT = 20). Analysis of J.M.'s urine samples over the first 18 days showed excretion patterns of glucuronide, sulfate, and glutathione derived cysteine and mercapturic acid conjugates were similar to the other subjects in the study. Acetaminophen causes hepatotoxicity in overdose or malnourished or alcoholic patients, none of which applied to our subject. Differences in metabolic activation and capacity for glutathione synthesis can predispose individuals given therapeutic doses of acetaminophen to adverse effects. Failure to detoxify a highly reactive metabolite, formed by P-450 metabolism, via glutathione conjugation is responsible for the development of acute hepatic necrosis. Accumulation of the toxic metabolite due to depleted glutathione stores may have occurred with prolonged high dosing in our subject and been responsible for his abnormal rise in liver enzymes.

Spironolactone pharmacokinetics and pharmacodynamics in patients with cirrhotic ascites.

The intent of this study was to identify pharmacokinetic and pharmacodynamic characteristics for spironolactone (SP) and its metabolites (canrenone, 6 beta-hydroxy-7 alpha-thiomethylspirolactone, 7 alpha-thiomethylspirolactone) in cirrhotics under steady state conditions. Nine cirrhotics with ascites participated in the study. Serial blood samples were drawn and urine was collected over a 26-hour period. Using a reverse-phase high performance liquid chromatography (HPLC) method, all samples were analyzed for SP, canrenone, 6 beta-hydroxy-7 alpha-thiomethylspirolactone, and 7 alpha-thiomethylspirolactone concentrations. Parent compound and metabolite urinary excretion rates as well as maximal concentrations and time at which these are observed were calculated. The apparent median terminal elimination rate constants (associated half-lives) were 0.0767 h-1 (9.04 hours) for SP, 0.0055 h-1 (126 hours) for 6 beta-hydroxy-7 alpha-thiomethylspirolactone, 0.029 h-1 (23.9 hours) for 7 alpha-thiomethylspirolactone and 0.012 h-1 (57.8 hours) for canrenone. SP metabolism is impaired in cirrhosis; terminal half-lives of SP and metabolites appear to be increased when compared with values reported in the literature for normals. When assuming a linear model, clearance-effect relationship estimates are best correlated with 7 alpha-thiomethylspirolactone and canrenone. Further research is required to identify specific pharmacokinetic and pharmacodynamic parameters for SP and its metabolites in this patient population.

Effect of indomethacin on the pharmacokinetics and pharmacodynamics of felodipine.

1. We studied the effects of pre-treatment with oral indomethacin (25 mg four times daily for 3 days) on the pharmacokinetics, haemodynamics and diuretic properties of oral felodipine (10 mg single dose) in 12 healthy male volunteers using a placebo controlled double-blind four-way crossover protocol. 2. Felodipine with or without indomethacin pretreatment reduced standing diastolic blood pressure (P less than 0.001) at 0.5 to 3.0 h after dosing compared with placebo or indomethacin alone. Systolic blood pressures during indomethacin treatment alone were consistently higher than the other three treatment groups (P less than 0.01), presumably due to sodium and fluid retention. 3. Felodipine and felodipine plus indomethacin produced significantly greater excretion of urine and urinary sodium, but not of urinary potassium or creatinine when compared with placebo (P less than 0.01) over an 8 h period. 4. The pharmacokinetic parameters of felodipine (Cmax, tmax, t1/2 and AUC), the concentration-response curves for blood pressure lowering effects, the reflex tachycardia, diuretic properties and side-effects profile of felodipine were not significantly altered by indomethacin pretreatment in normal volunteers.

Interindividual and intraindividual variability in acetylation: characterization with caffeine.

The degree of interindividual and intraindividual variability in acetylator activity was investigated with caffeine used as a probe of enzyme activity. Acetylator phenotype and relative N-acetyltransferase activity were estimated in 46 subjects by measuring the urinary ratio of two metabolites, AFMU/1-MX, after a single 300 mg oral dose of caffeine on five separate occasions. Thirty homozygous slow (rr) and 15 heterozygous rapid (Rr) acetylators were identified. The degree of interindividual variability in acetylator activity was observed to be a mean of 32% (range 27% to 36%) and 20% (range 11% to 29%) in the rr and Rr groups, respectively. The mean intraindividual variation on repetitive measurement was 19% (range 6% to 49%) in the rr and 14% (range 7% to 24%) in the Rr acetylator group. Four subjects had apparent changes in acetylator activity with time such that they were unable to be assigned to any one acetylator group. Two of these four subjects exhibited apparent homozygous rapid acetylator activity intermittently during the 5-week trial. This variability may explain, in part, some of the high degree of patient variability observed in the toxicity, efficacy, and drug-related disease associated with acetylated drugs and environmental toxins.

Rectal absorption of propylthiouracil.

The rectal absorption of propylthiouracil (PTU) was studied and compared to oral absorption in normal volunteers. Plasma levels of PTU after administration of suppositories of PTU base and PTU diethanolamine were significantly lower compared to the oral route. Elevated plasma reverse T3 levels were demonstrated after each treatment, however, suggesting a desirable therapeutic effect at this dosage level for all preparations.

Nonsteroidal anti-inflammatory drugs and gastrointestinal bleeding. A case-control study.

This study looked at the association between nonsteroidal anti-inflammatory drug (NSAID) use and acute nonvariceal upper gastrointestinal tract bleeding (AUGIB). Fifty-seven consecutive patients presenting to hospital with AUGIB were compared with 123 sex- and age-matched controls. Twenty-four (42.1%) of the 57 AUGIB patients were taking NSAIDs compared with 23 (18.1%) of the 123 control subjects. Patients whose AUGIB was associated with NSAID use were significantly older than the group whose bleeding was not associated with drug use; no other differences between these two groups was found. Seventy percent of patients taking nonacetylsalicylic acid who developed bleeding in this study did so within three months of starting therapy. Abdominal pain was an infrequent presenting complaint.

Disulfiram-induced hepatitis. Report of two cases and review of the literature.

Two cases of disulfiram-induced hepatitis are presented. Both cases had prompt recurrence of abnormal liver function tests after rechallenge with small doses of the drug. All cases of disulfiram-induced hepatotoxicity reported in the English literature are reviewed.

Effect of low-dose cimetidine on theophylline metabolism.

The effect of low doses of cimetidine on theophylline clearance and metabolism was studied. In a randomized, crossover study, 10 healthy men received oxtriphylline alone or with cimetidine. Oxtriphylline 200 mg (equivalent to theophylline 135 mg) was given orally every eight hours for 10 doses. Cimetidine 300 mg was given orally at bedtime for four days, beginning the same day as oxtriphylline treatment. At least 10 days separated study periods. In each study period, blood samples for plasma theophylline determinations were drawn 24 hours before the last dose of oxtriphylline, at the time of the last dose, and periodically up to 32 hours after the last dose. A 24-hour urine collection for quantification of theophylline and metabolite excretion was started at the time of the last oxtriphylline dose. Plasma theophylline clearance decreased significantly by a mean of 12.2% during cimetidine treatment. Area under the curve showed a significant mean increase of 17.4%. Increases in clearance and area under the curve values occurred in 9 of 10 subjects. In 6 of 10 subjects who had increases in theophylline trough concentrations, the mean increase was 28.2%; when all 10 subjects were considered, however, the mean increase was 10.3%, which was not significant. No significant differences in the urinary recoveries of theophylline or its metabolites were noted between study periods. Because of the decreases in theophylline clearance produced by low doses of cimetidine in this study, clinicians should monitor for potential theophylline toxicity in patients who receive these drugs concomitantly.

Dose-dependent effect of cimetidine on phenytoin kinetics.

Eight normal subjects were given 250 mg intravenous phenytoin alone and with 3-day regimens of oral cimetidine, 400 mg at bedtime, 1200 mg a day, and 2400 mg a day in a randomized crossover fashion. Plasma samples for phenytoin and cimetidine, and urinary concentrations for phenytoin and 5-(4-hydroxyphenyl)-5-phenylhydantoin (HPPH) were measured by HPLC. All cimetidine regimens decreased phenytoin clearance, and there was no difference between the 400-mg bedtime dose and the 1200-mg a day regimens. There was, however, a difference between the 400-mg and 1200-mg and the 2400-mg regimens. There was no linear correlation between steady state cimetidine plasma concentrations and the decrease in phenytoin clearance. Urinary HPPH/phenytoin ratios decreased with all cimetidine treatments, but the differences were not significant. Phenytoin toxicity may result when cimetidine is added to existing regimens of this anticonvulsant.