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The effect of sulphinpyrazone administration on the anticoagulant response was investigated in five patients receiving long-term treatment with warfarin. Sulphinpyrazone caused a rapid increase in prothrombin (PT) ratio in all five patients and warfarin dose had to be reduced by a mean of 46% to maintain the PT ratio in the therapeutic range. PT ratio and daily warfarin requirement returned to previous levels when sulphinpyrazone was ceased. Warfarin protein binding was not altered during sulphinpyrazone administration and sulphinpyrazone added to plasma in vitro did not increase warfarin free fraction. The average racemic plasma warfarin concentration over a dosage interval when adjusted for warfarin dose was not altered by sulphinpyrazone administration. The most likely mechanism for this drug interaction is a stereoselective effect of sulphinpyrazone on the metabolism of the warfarin enantiomers.

Plasma concentrations were measured in 10 patients with rheumatoid arthritis taking 250 mg, 500 mg and 750 mg of D-penicillamine daily. A disproportionate rise in the dose adjusted area under the plasma concentration vs time curve suggested dose dependent kinetics for D-penicillamine. Marked interindividual variability was seen with pharmacokinetic parameters and no correlations were observed between side effects or response and plasma concentrations of reduced D-penicillamine.

The caffeine content of all tea or coffee beverages consumed by 17 healthy adults over 24 hours was measured. Plasma caffeine, theophylline, theobromine, and paraxanthine concentrations were determined over the same 24 hours. The average caffeine content per drink was 60.4 +/- 21.8 mg for instant coffee (14-fold range), 80.1 +/- 19.2 mg for brewed coffee (2.8-fold range), and 28.8 +/- 13.7 mg for tea (5.5-fold range). The number of drinks of coffee and tea consumed was a poor index of actual caffeine intake (r2 = 0.42). Caffeine intake correlated poorly with the 24-hour average caffeine concentration (r2 = 0.41), but there was a very good correlation between a single plasma caffeine concentration measured at 5 PM and the 24-hour average concentration (r2 = 0.94). The same was true for paraxanthine (r2 = 0.86). Paraxanthine accounted for 67.3% of the total dimethylxanthines in plasma, while theobromine and theophylline accounted for 24.4% and 8.3%, respectively. Mean caffeine clearance was 1.2 +/- 0.3 ml/min/kg. Plasma caffeine concentration before the first drink in the morning correlated very poorly with caffeine clearance (r2 = 0.07), even when adjusted for caffeine intake (r2 = 0.21).

Aspirin (acetylsalicylic acid) is metabolically converted to salicyclic acid by the action of carboxylesterases. Although metabolic drug interactions involving aspirin are theoretically possible, there appear to have been no studies to date which have shown conclusively that aspirin hydrolysis is altered by coadministered drugs. However, a number of treatments are known to affect the rate or extent of aspirin absorption, including activated charcoal, antacids, cholestyramine and metoclopramide. Caffeine and metoprolol have been reported to increase peak salicylic acid concentration following aspirin administration, and coadministration of dipyridamole and aspirin results in higher plasma aspirin concentrations. The mechanism(s) responsible for these latter observations remains unknown. Salicylic acid is extensively bound to plasma albumin, and many of the reported drug interactions involve displacement of the coadministered drug from plasma protein. Protein binding displacement appears to be the basis of salicylic acid interactions with diclofenac, flurbiprofen, ibuprofen, isoxicam, ketoprofen, naproxen, phenytoin and tolmetin. Following displacement of these agents increased clearance of total drug occurs, and consequently the plasma concentration of total drug decreases. Although generally not measured, unbound concentration of the interacting drug should not be markedly altered. Salicylic acid also increases total plasma clearance of fenoprofen but, unlike the interactions with the other propionic acid non-steroidals, plasma protein binding displacement does not appear to be involved. Induction of fenoprofen metabolism is a possibility, although there is no firm evidence from other studies that salicylate is able to induce the metabolism of coadministered drugs. Since salicylic acid is extensively metabolised, it is not surprising that it is able to inhibit the metabolism of certain coadministered drugs and chemicals, an effect which has been reported for salicylamide, valproic acid, m-xylene, and zomepirac. The interactions with salicylamide, m-xylene and zomepirac are probably competitive in nature since mutual inhibition of salicylic acid metabolism occurs. There is an additional component of protein binding displacement in the interactions with valproic acid and zomepirac, resulting in increased unbound drug concentration. Certain coadministered drugs (or chemicals) may alter the metabolism of salicylic acid; inhibition of its metabolism has been demonstrated following treatment with benzoic acid, salicylamide, m-xylene, zomepirac and possibly cimetidine. In contrast, salicylic acid elimination is enhanced in oral contraceptive steroid users and by corticosteroid treatment. Oral contraceptive steroids induce both salicylic acid glucuronidation and salicylurate formation. Induction of metabolism has also been proposed to account for the effects of corticosteroids, but this is still to be proven.(ABSTRACT TRUNCATED AT 400 WORDS)

Procedures based on high-performance liquid chromatography (HPLC) were developed for identifying and measuring p-aminobenzoic acid (PABA) and its conjugate metabolites in human urine after oral doses of PABA. p-Aminohippuric acid (PAH), PABA, p-acetamidohippuric acid (PAHA) and p-acetamidobenzoic acid (PADB) in urine were resolved and determined by HPLC simultaneously and directly without extraction. A mobile phase consisting of 3% (v/v) acetonitrile in distilled water containing 0.005 M 1-heptanesulphonic acid in glacial acetic acid (PIC-B7) at pH 3.3 was eluted at 1 ml/min through a C18 Spherisorb column, followed by UV detection at 280 nm. After hydrolysis of urine samples at 37 degrees C for 3 h with beta-glucuronidase, the amounts of PABA-glucuronide and PADB-glucuronide were also determined. The retention times of PAH, a dominant peak which disappeared after hydrolysis, PABA, DABA (3,5-diaminobenzoic acid, as the internal standard), PAHA and PADB were 11.8, 14, 15, 18, 24 and 46 min, respectively. The 24-h urinary recoveries of PAH, PAHA, PADB, PADB-glucuronide, PABA and PABA-glucuronide after separate oral doses of 200 and 800 mg of PABA in one healthy subject were 43.4 and 48.1, 7 and 29.1, 11.2 and 11.8, 34.8 and 6.6, 0.2 and 0.3, and 1.0 and 2.4%, respectively. It is interesting that at high dose (800 mg) saturation of glucuronidation of PADB (N-acetylated PABA) appeared to occur, which resulted in an increase in the formation of PAHA, the glycine conjugate of PADB. Over 90% of the oral dose was accounted for by 8 h after administration.

Theobromine metabolism and clearance were investigated at steady-state under chronic oral dosing conditions in eight healthy volunteers, four of whom were cigarette smokers. The subjects were studied before and after separate 1 week pretreatments with cimetidine (1 g/day) and sulfinpyrazone (800 mg/day). Theobromine plasma clearance (ClTB) was 33% higher in smokers than in non-smokers due to induction of all metabolic pathways (3-demethylation, 7-demethylation, and formation of 6-amino-5-(N-methylformylamino)-1-methyluracil (AMMU]. 7-Demethylation was induced by cigarette smoking to a greater extent than the other pathways. Cimetidine pretreatment inhibited theobromine 3-demethylation and AMMU formation resulting in a 27% decrease in ClTB in the combined smoker/nonsmoker group. The 7-demethylation pathway was unaffected by cimetidine. In contrast, sulfinpyrazone pretreatment increased ClTB by 50% in the whole group by approximately equal induction of each metabolic pathway. The extent of induction due to sulfinpyrazone was 2.4-fold greater in nonsmokers than in smokers. When compared with previous data relating to theophylline, the results suggest that theobromine 3-demethylation is mediated by the same form(s) of cytochrome P-450 involved in theophylline demethylation, while a second form(s) of cytochrome P-450 is involved in theobromine 7-demethylation and theophylline 8-hydroxylation. In addition, since AMMU formation was inhibited by cimetidine and induced by cigarette smoking and sulfinpyrazone, it would appear that the conversion of theobromine to AMMU is also mediated by cytochrome P-450.

We report a "high-performance" liquid-chromatographic method for measuring 5-fluorocytosine in plasma and cerebrospinal fluid. After deproteinization with trichloroacetic acid, the supernates are chromatographed on a reversed-phase (C18) column. Response to concentration is linear in the range of 5 to 200 mg/L, with ultraviolet detection at 276 nm. The assay requires only 0.1 mL of plasma, is reproducible, and may be performed in less than 12 min. 5-Fluorocytosine concentrations determined by this procedure correlated well with those obtained by spectrofluorometry, although the present method is more specific with no observable interference from co-administered amphotericin B and most other commonly encountered drugs, including salicylat:. This method is applicable to the routine therapeutic monitoring of pediatric and adult patients as well as to pharmacokinetic studies.

Increasing concern about caffeine as a drug with potential for abuse has resulted in the development of procedures for effecting reductions in caffeine consumption among heavy users. However, the reliability of reported findings may be questioned, since previous studies have relied on subject self-report as the principal measure of caffeine use. The present study employed bioanalytic methods for assessing the reliability of self-reported caffeine intake during a caffeine-fading regime. Twelve subjects, each with a history of heavy caffeine use, provided baseline, treatment, and follow-up blood samples which were assayed for caffeine and its major metabolites. General support was provided for the reliability of self-report as a measure of caffeine consumption. The general efficacy of caffeine fading was also supported, although there were indications that maintenance effects may have been over-estimated in previous studies.

Acetaminophen metabolism and clearance after a single 1 gm oral dose of the drug was investigated in 12 healthy men, six of whom were cigarette smokers, and in six men who were receiving anticonvulsant drugs for epilepsy. The 12 healthy subjects were studied before and after 1 wk of pretreatment with cimetidine (1 gm/day) or sulfinpyrazone (800 mg/day). There was no significant difference in acetaminophen clearance (ClAP) between nonsmokers and smokers; cimetidine pretreatment had no effect on ClAP. Neither cigarette smoking nor cimetidine pretreatment had a significant effect on any of the metabolic pathways of acetaminophen. In contrast, sulfinpyrazone pretreatment increased ClAP by 23% (from 5.70 +/- 0.21 to 7.00 +/- 0.39 ml/min/kg) and ClAP was 46% greater in the epileptic subjects who received anticonvulsant drugs than in the control group (8.32 +/- 0.45 and 5.70 +/- 0.21 ml/ml/kg). In both cases the increase in ClAP was a result of induction of acetaminophen glucuronidation and oxidation; clearance of the glucuronic acid conjugate was 26% and 59% greater and clearance of the glutathione-derived conjugates (reflecting the activity of the oxidative pathway) was 43% and 60% greater in the groups given sulfinpyrazone and anticonvulsants, respectively.

The capacity of human, rabbit and rat liver microsomes and purified isozymes of cytochrome P450 to metabolize theophylline has been assessed. In all three species the 8-hydroxylation of theophylline to 1,3-dimethyluric acid (1,3-DMU) was the major pathway. In human, control rabbit and rat liver microsomes this metabolite accounted for 59, 77 and 94%, respectively, of the total metabolites formed. In both human and control rabbit liver microsomes the N-demethylation of theophylline to 1-methylxanthine (1-MX) accounted for 20% of the total metabolites formed. N-demethylation of theophylline to 3-methylxanthine (3-MX) accounted for 21% of theophylline metabolism in human microsomes but was a minor pathway in control rabbit and rat microsomes. Acetone and phenobarbitone pretreatment markedly increased the formation of 1,3-DMU by rabbit liver microsomes. Rifampicin and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) administration caused a slight but significant increase in this pathway. In general the N-demethylation pathways in rabbit liver microsomes were refractory to induction. In the rat, the metabolism of theophylline to 1-MX, 3-MX and 1,3-DMU were all significantly increased in Aroclor 1254, dexamethasone, phenobarbitone and 3-methylcholanthrene-treated microsomes. In reconstitution experiments the polycyclic hydrocarbon inducible rabbit cytochrome P450 Forms 4 and 6 and the constitutive Form 3b all metabolized theophylline to its three metabolites. In human liver microsomes from four subjects anti-rabbit cytochrome P450 Form 4 IgG inhibited the metabolism of theophylline to 1-MX, 3-MX and 1,3-DMU by approximately 30%. These data indicate that theophylline is metabolized by multiple forms of cytochrome P450 in human, rabbit and rat liver microsomes.

The mechanism of action of cysteine, methionine, N-acetylcysteine (NAC) and cysteamine in protecting against paracetamol (APAP) induced hepatotoxicity in male C3H mice in vivo has been investigated by, characterising the effect of the individual protective agents on the metabolism of an hepatotoxic dose of APAP, and determining the efficacy of the protective agents in animals treated with buthionine sulphoximine (BSO), a specific inhibitor of glutathione (GSH) synthesis. Co-administration of cysteine, methionine or NAC increased, while co-administration of cysteamine decreased, the proportion of GSH-derived conjugates of APAP excreted in the urine of mice administered APAP, 300 mg/kg. Pretreatment of animals with BSO abolished the protective effect of cysteine, methionine and NAC, whereas cysteamine still afforded protection against APAP after BSO treatment. In conjunction with other data, these results suggest the most likely mechanism for the protective effect of cysteine, methionine and NAC is by facilitating GSH synthesis, while the most likely mechanism for the protective effect of cysteamine is inhibition of cytochrome P-450 mediated formation of the reactive metabolite of APAP.

GP53,633 is a new basic non-steroidal anti-inflammatory drug showing analgesic and anti-inflammatory activity in animal models. Pharmacokinetic studies in 6 patients with rheumatoid arthritis show it to be rapidly absorbed with a short half life (approximately 2 hours). No change in pharmacokinetics is seen over a two week treatment period. Clinical parameters of inflammation were reduced and no adverse reactions were seen.

The total plasma and partial metabolic and renal clearances of theobromine and theophylline were determined in 13 healthy volunteers. Total plasma clearance for theobromine was 46% greater than that for theophylline, but the unbound clearances were almost identical. Theobromine renal clearance was 67% greater than that for theophylline but most of the difference was due to the lower protein binding of theobromine (free fraction = 0.86 compared to 0.58 for theophylline). Clearance by N-demethylation at the 3-position was 3.7-fold higher (unbound clearance 2.5-fold higher) for theobromine than for theophylline, showing that the position of the other methyl substituent (positions 1 or 7) is a major determinant of metabolic rate. There was a high degree of correlation between theophylline and theobromine plasma clearances (r = 0.86) and also between partial metabolic clearances both within drugs and across drugs (r = 0.65-0.99). The renal clearances of theophylline and theobromine were also correlated (r = 0.71). The results support the view that theophylline and theobromine are metabolized by a common group of cytochromes P-450 under similar regulatory control. Theobromine is a good model compound for assessing the activity of these enzymes in man as it has low pharmacological activity and low protein binding, its total and partial metabolic clearances correlate closely with those of theophylline, and close to 100% of the dose can be recovered as known metabolites.