Disposition and oxidative metabolism of phenylbutazone in man

Summary The absorption and elimination of orally administered¹⁴C-phenylbutazone and the role of oxidation in its metabolism have been studied. The main routes of excretion of¹⁴C-phenylbutazone and its metabolites were investigated in 3 patients with rheumatoid arthritis, and in 1 patient with a T-tube in the common bile duct. Up to 9 days after an oral dose of¹⁴C-phenylbutazone 600 mg (30 µCi) 63% of the radioactivity was found in the urine and 14% had appeared in the faeces. The cumulative excretion of radioactivity in bile amounted to 9.5% of the dose in 4 days. Only 1% of the radioactivity in the urine and bile was due to unchanged phenylbutazone. The role of oxidative metabolism of phenylbutazone in healthy human subjects was studied by gas chromatography. In 3 subjects given a single dose of phenylbutazone 600 mg, only 8.3% of the dose was excreted in urine as oxidized metabolites after 5 days. However, in 5 patients who had taken phenylbutazone for more than 5 weeks, these metabolites accounted for 23.4% of the dose. These results suggest that oxidative metabolism becomes more important after continued administration of the drug. After a single dose of phenylbutazone, the side-chain oxidized metabolite (II) was the major free derivative excreted in urine, but the ring oxidized metabolite, oxyphenbutazone (I), was much more important than the former in plasma. However, after prolonged treatment there was little difference between the concentration of the two metabolites in plasma. This finding suggests that side-chain oxidation is increased relative to ring oxidation on prolonged treatment with phenylbutazone. A third derivative containing hydroxyl groups both in the phenyl ring and in the side-chain (metabolite III) was found in urine in experiments with phenylbutazone, but in only one out of 3 volunteers given repeated doses of oxyphenbutazone.     

Pharmacokinetics of diazepam in epileptic patients and normal volunteers following intravenous administration

1 The pharmacokinetics of diazepam following intravenous administration have been investigated in six normal volunteers and nine epileptic patients receiving chronic antiepileptic drug therapy. 2 After intravenous administration, serum diazepam levels declined biexponentially in all subjects. The elimination half-life was significantly shorter and the plasma clearance significantly higher in the patients than in the normal volunteers. 3 Serum N-desmethyldiazepam levels were higher and the time to peak serum concentration was earlier in the epileptic patients than in the controls. 4 It is suggested that the metabolism of diazepam is induced in patients treated with enzyme inducing antiepileptic drugs, although a protein binding interaction between valproic acid and diazepam may contribute to the higher plasma clearance in the epileptic patients taking sodium valproate.     

Effects of a mixture of two insecticides in freshwater microcosms: I. Fate of chlorpyrifos and lindane and responses of macroinvertebrates

Effects of chronic application of a mixture of the insecticides chlorpyrifos and lindane were studied in indoor freshwater microcosms. The exposure concentrations (based on 0, 0.005, 0.01, 0.05, 0.1 and 0.5 times the LC50 of the most sensitive standard test organism for each compound) were kept at a constant level for four weeks. The calculated mean concentrations for chlorpyrifos were found to be almost at their corresponding nominal level during the treatment period. The mean calculated lindane concentrations, however, were found to be 15–40% higher than intended. In the post treatment period both insecticides dissipated fast (t _1/2: chlorpyrifos 9 days, lindane 22 days) from the water phase. The concentrations of the mixture at the highest treatment level corresponded to 0.53 toxic units (TU) for Daphnia magna and 0.61 TU for the most sensitive fish. The decomposition of Populus leaves in litter bags was significantly lower at the three highest insecticide concentrations. The macroinvertebrate community was seriously affected at the three highest treatment levels, with Crustacea and the Chironomidae Corynoneura proving to be the most sensitive groups. Gastropoda and Oligochaeta were relatively insensitive and some taxa (e.g. Valvata piscinalis, juvenile Physa fontinalis, Nemertea and Stylaria lacustris) increased in numbers. The observed effects could be explained from the individual toxicity of the insecticides to the invertebrates, and did not indicate synergistic effects. A second paper (Van den Brink et al., 2002) addresses the effects on other endpoints, as well as the overall risk assessment of the insecticide mixture.     

The influence of allopurinol and size of dose on the metabolism of phenylbutazone in patients with gout

Summary Administration of allopurinol 300 mg/day produced minimal changes in the disappearance of phenylbutazone in each of five subjects following single doses (6 mg/kg) in clinical range and caused some prolongation (21%, 52%) of drug half-lives in two of six subjects after single small doses (0.5 mg/kg); mean half-life was not significantly altered by allopurinol at either dose level (means of 52 versus 48 at 0.5 mg/kg and 68 versus 70 h at 6 mg/kg). Size of dose altered half-life when phenylbutazone was used alone; three subjects showed considerably longer half-lives at the higher dose (86 versus 47, 91 versus 41, 65 versus 38 h). Allopurinol caused a greater than 50% prolongation of half-lives in two of five subjects who received single 0.5 g doses of probenecid. These preliminary data do not indicate a need to change the dose of phenylbutazone when subjects are receiving allopurinol.     

Pharmacokinetics of loprazolam and its principal metabolite in young subjects and elderly hospital patients

1. The pharmacokinetics of loprazolam and its principal pharmacologically active metabolite, the piperazine N-oxide, were compared in young subjects (aged 21–25 years) and elderly patients (aged 63–86 years) following single oral evening doses (0.5 mg and 1 mg).

2. Plasma loprazolam was assayed by a specific h.p.l.c./g.c. method. The N-oxide metabolite was assayed by gas chromography.

3. Mean times to peak plasma concentration of loprazolam did not differ significantly between young and elderly subjects and ranged from 1.6–2.7 h. There was, however, a longer mean time to peak concentration of the N-oxide metabolite in the elderly but this was only statistically different after the 0.5 mg dose (4.5 mg young, 6.4 h elderly).

4. Mean peak plasma concentrations of loprazolam did not differ significantly between young and elderly nor did plasma concentrations of the N-oxide metabolite.

5. Although the mean elimination half-life of loprazolam was not statistically signiticantly different between young and elderly subjects (range 10.9–16.0 h) there was a trend towards somewhat longer half-lives in the elderly. Furthermore, there was a small but significant increase in the half-life of the N-oxide metabolite in the elderly after the 1 mg dose from 11.7 h to 16.7 h.

6. The areas under the plasma concentration time curves for both loprazolam and its N-oxide were greater in the elderly being some 50–68% (mean 132.0 and 111.5 ng/ml h) above those found in young subjects (mean 89.8 and 66.0 ng/ml h).

7. Despite these changes the maximum accumulation ratio predicted from these single dose studies would be 1.16 in the young and 1.40 h in the elderly, assuming once nightly dosing.     

Bioavailability of phenylbutazone from a new enteric-coated formulation with superior dissolution characteristics

The bioavailability of an improved formulation of enteric-coated phenylbutazone with faster dissolution, more consistent in vitro rate of drug release and improved stability was compared in 8 normal subjects at doses of 100 and 200 mg with commercially available Butacote®. Phenylbutazone was more rapidly absorbed from the new formulation and higher plasma concentrations were achieved at shorter intervals after dosing. Drug elimination rate was unaffected by reformulation and despite faster absorption the total amounts of drug reaching the circulation from the new and commercial products were similar. It was concluded that replacing Butacote® by the new formulation would provide the same therapeutic benefit.     

Pharmacokinetics of intranasal,intramuscular and intravenous glucagon in healthy subjects and diabetic patients

Summary The pharmacokinetics of intranasal, an intravenous infusion, and intramuscular glucagon has been studied in 5 healthy subjects and 11 patients with insulin-dependent diabetes mellitus.After infusion the elimination half-life was significantly longer in diabetics (11.9 vs 6.6 min) and the apparent volume of distribution was twice as high in diabetics (0.19 vs 0.37 l·kg^–1). The metabolic clearance rates were the same in the two groups (18.9 and 21.3 ml·min^–1·kg^–1 in controls and in diabetics) and were about twice those previously reported.After 1 mg intranasally the C_max of immunoractive glucagon (IRG) was similar in diabetic and in healthy subjects. Administration of a higher dose (2 mg) to diabetic patients produced a higher plasma level, although not proportionately so. The AUC after 1 mg was also similar in controls and in diabetics. The elimination half-life in both groups was similar to the value found after IV infusion; it was significantly shorter in controls (5.5 min) than in diabetics (13.8 min). In both groups, mean C_max was significantly lower than after IM glucagon, the relative bioavailability of 1 mg intranasally vs IM injection being less than 30%.After IM administration, the C_max and AUC of IRG in controls and in diabetic patients, were identical. The apparent elimination half-life was also similar in the two groups, and was three- to four-times longer (28.6 and 31.4 min) than after infusion or intranasal administration, possibly because estimation of the t_1/2 was affected by slow release of the hormone from the site of injection.     

Phenobarbital-induced drug metabolism in man

Phenobarbital and antipyrine half-lives were measured in 31 subjects. A high correlation (r = 0.87) was found for the plasma elimination rates of the two drugs, suggesting the same or a similar route or a common regulatory control of their metabolism. The half-lives of phenobarbital and antipyrine also correlated highly with the aryl hydrocarbon hydroxylase (AHH) inducibilities in mitogen-stimulated lymphocytes of the same individuals. In the second part of the study, plasma antipyrine half-lives were measured in 22 subjects after a single oral dose of 18 mg/kg, and the AHH inducibilities were determined in their cultured lymphocytes. After 7 days on phenobarbital at aryl hydrocarbon hydroxylase inducibilityadjusted doses ranging between 1.0 and 2.0 mg/kg daily, the antipyrine half-lives were measured again and the percentage of decrease between the initial and second antipyrine half-lives was determined. Shortening of the plasma half-lives occurred in all subjects to various degrees, ranging between 13.3 and 30.6%. However, under our experimental conditions in which the dose of phenobarbital was adjusted to the individual rates of metabolism of the inducing agent, no relationship could be found between the initial antipyrine half-life and the percentage of shortening of its plasma half-life, such as had been reported by several authors.     

Theophylline kinetics in relation to age: the importance of smoking.

1 Single dose studies of theophylline kinetics were compared in groups of young and elderly smokers and non-smokers to assess the effect of age on theophylline absorption and the effect of smoking on drug metabolising enzyme activity in old age. 2 The rate and extent of absorption was not affected by age. Distribution and elimination kinetics were similar in young and elderly non-smokers. 3 In young subjects the elimination half-life of theophylline was shorter and clearance was significantly greater in smokers than in non-smokers. 4 In the elderly mean elimination half-life was significantly shorter in smokers and their plasma clearance was 40% higher than in non-smokers. The statistical difference for clearance was at the 7% level of significance. 5 These data indicate that ageing per se does not affect theophylline elimination and also that induction of theophylline metabolism due to smoking occurs in old age. Smoking is a variable that should be taken account of when assessing drug metabolism in elderly patients.     

Interaction of phenylbutazone with racemic phenprocoumon and its enantiomers in rats

The interaction of phenylbutazone with the enantiomers and racemic [ ³ H]phenprocoumon was studied in male inbred Wistar-Lewis rats following a single i.v. dose of the three forms of phenprocoumon and chronic oral treatment with phenylbutazone (average plasma concentration of about 60 g/ml). Phenylbutazone augmented the anticoagulant effect of R(+), S(–), and R, S (±) phenprocoumon to a similar extent. The free fraction of drug in the plasma of the enantiomers and racemic phenprocoumon increased in the presence of phenylbutazone. However, the rate of elimination of total drug from plasma and liver and the distribution between liver and plasma of all three forms of phenprocoumon remained nearly unaffected by phenylbutazone. Thus there is no evidence for a stereoselective drug interaction between phenprocoumon and phenyl-butazone. For racemic [ ³ H]phenprocoumon it was possible to follow the kinetics of free drug in plasma and liver along with the time course of anticoagulant activity. In these studies, free drug concentrations in plasma and liver increased during treatment with phenylbutazone, but the elimination rate constant of free racemic phenprocoumon in plasma and liver remained essentially unchanged. Phenylbutazone markedly decreased the volume of distribution referenced to free drug and the clearance of free phenprocoumon (i.e., intrinsic metabolic clearance). Whereas the total (bound and unbound) drug concentration-effect relationship in plasma and liver was shifted to the left in rats treated with phenylbutazone, such shift was not seen in the free drug concentration-response relationship. In conclusion, the increase in the free concentration of phenprocoumon in plasma and liver and the concomitant decrease in the clearance of free drug are the mechanisms responsible for the marked and sustained enhancement of the anticoagulant effect which follows treatment with phenbutazone.This work was supported by the Deutsche Forschungsgemeinschaft.     

Evaluation of the tear and serum levels of IL-8 in sulfur mustard intoxicated patients 20 years after exposure

Purpose: Delayed keratitis is the most dangerous ocular complication of sulfur mustard (SM) exposure. This study aimed to evaluate the role of tear and serum levels of interleukin-8 (IL-8) in SM exposed subjects. Design and methods: In this historical cohort study, the experimental group included 370 participants who had been exposed to SM 20 years prior. Data were compared with those of 128 unexposed participants as the control group. After completing a thorough systemic and ocular examination, serum IL-8 levels in all exposed and controls were compared. According to the statistical calculation, tear IL-8 levels, were compared in randomly selected 48 exposed and 37 controls. Based on the ocular findings, the selected subjects were divided into two subgroups, normal subjects include those participants who had no ocular signs and abnormal subjects, were those who had at least one or more ocular signs. Results: Bulbar conjunctiva and limbal tissues evaluation in all participants showed a significantly higher number of abnormalities in exposed group than in the control group (P?=?0.004 and P?=?0.048 respectively). Serum IL-8 levels in all exposed were significantly lower than the matched controls (P?=?0.002). Tear IL-8 levels in the selected exposed were significantly lower than in the selected controls (P?=?0.030). In exposed group with normal conditions of the lids, bulbar conjunctiva, cornea, tear status, limbus, slit lamp findings and final ophthalmic assessment, tear IL-8 levels were significantly lower than in the matched controls (P?=?0.022, 0.037, 0.027, 0.050, 0.039, 0.029, 0.045 respectively). With respect to the global ophthalmic assessment, tear fluid IL-8 levels in the abnormal controls were significantly lower than in the normal controls (P?=?0.049), but this decrease in secretion of tear IL-8 were not encountered in abnormal exposed (P?=?0.415). Conclusion: Tear IL-8 secretion was significantly inhibited in the unexposed controls with ocular surface abnormalities, while these inhibitory responses were not encountered in SM-exposed cases with ocular surface abnormalities.     

Parkinson's disease and CYP1A2 activity

AIMS MPTP, a neurotoxin which induces parkinsonism is partially metabolized by the enzyme CYP1A2. Smoking appears to protect against Parkinson's disease (PD) and cigarette smoke induces CYP1A2 activity. Thus, we investigated the hypothesis that idiopathic PD is associated with lower CYP1A2 activity using caffeine as a probe compound. METHODS CYP1A2 activity was assessed using saliva paraxanthine (PX) to caffeine (CA) ratios. Caffeine half-life was also estimated from salivary concentrations of caffeine at 2 and 5 h post dose. 117 treated and 40 untreated patients with PD and 105 healthy control subjects were studied. RESULTS PX/CA ratios were 0. 57, 0.93 and 0.77 in treated patients, untreated patients and healthy control subjects, respectively, with no significant differences between study groups (95% CI: treated patients vs controls -0.24, 0.57; untreated patients vs controls -0.75, 0.35). However, patients with PD (treated or untreated) had caffeine half-lives shorter than that in controls (treated patients: 262 min, untreated patients: 244 min, controls: 345 min; 95% CI: controls vs treated patients 23, 143 (P = 0.003); controls vs untreated patients 19, 184 (P = 0.011)). Amongst the patients with PD, caffeine half-life was also inversely related to the age of onset of disease (P = 0.012); gender and concomitant drugs did not influence this significantly. CONCLUSIONS: Based on PX/CA ratio, there was no evidence of decreased CYP1A2 activity in patients compared with control subjects. The observed decrease in the elimination half-life of caffeine in PD may be caused by increased CYP2E1 activity, an enzyme that also contributes to the metabolism of caffeine. The latter warrants further investigation.     

Differential effect of Type I and Type II diabetes on antipyrine disposition in man

Summary As the influence of diabetes on drug metabolism in patients is controversial, a study was performed to assess antipyrine (AP) disposition in controlled Type I and Type II diabetics and 2 age-and sex-matched control groups. In Type I diabetics, the half-life of AP was significantly reduced from 12.0 (controls) to 7.9 h, and the volume of distribution (V) was lowered from 733 to 569 ml·kg^–1. The resulting plasma clearance and cumulative urinary excretion of AP and its metabolites over 24 h did not differ from controls. In Type II diabetics, the AP half-life (14.5 h) and V (568 ml·kg^–1) did not differ from their age- and sex-matched controls (11.1 h and 643 ml·kg^–1, respectively), but the plasma clearance of AP was significantly reduced by 30%, and urinary excretion was significantly reduced to 44% of controls.The differential effects of Types I and II diabetes on AP metabolism may explain, at least in part, the controversial data in the literature.     

Ontogenetic influence on rat susceptibility to lindane seizure after pretreatment with phencyclidine

The aim of the study was to determine the effects of early postnatal PCP treatment on the sensitivity of pubertal and adult rats to lindane proepileptogenic effects. Rat pups were treated with NaCl (0.9%) or PCP (10 mg/kg) at postnatal days 2, 6, 9 and 12. One control (NaCl-35) and one experimental (PCP-35) group have received lindane (4 mg/kg) at postnatal day 35, while others received lindane at postnatal day 65 (NaCl-65 and PCP-65). One week prior to lindane treatment three gold-plated EEG electrodes were implanted. Pubertal rats had significantly shorter latency time. After lindane, a prompt increase in power spectral density seen in PCP-treated groups vs. control was evident earlier in PCP-65 rats. The theta waves were significantly increased in PCP-35 and alpha rhythm in PCP-65 rats, when compared with corresponding controls. Postnatal PCP treatment increases the synchronization of brain electrical activity, thus contributing to the increased susceptibility to lindane.     

Disposition and metabolism of [14C]-galunisertib,a TGF-βRI kinase/ALK5 inhibitor,following oral administration in healthy subjects and mechanistic prediction of the effect of itraconazole on galunisertib pharmacokinetics

1.?The disposition and metabolism of galunisertib (LY2157299 monohydrate, a TGF-βRI Kinase/ALK5 Inhibitor) was characterized following a single oral dose of 150?mg of [¹⁴C]-galunisertib (100?µCi) to six healthy human subjects.

2.?The galunisertib plasma half-life was 8.6?h, while the ¹⁴C half-life was 10.0?h. Galunisertib was abundant in circulation (40.3% of the ¹⁴C AUC024?h), with 7 additional metabolites detected in plasma. Two metabolites LSN3199597 (M5, mono-oxidation), and M4 (glucuronide of M3) were the most abundant circulating metabolites (10.7 and 9.0% of the 14C AUC024?h respectively). The pharmacological activity of LSN3199597 was tested and found to be significantly less potent than galunisertib.

3.?The dose was recovered in feces (64.5%) and in urine (36.8%). Galunisertib was cleared primarily by metabolism, based on low recovery of parent in excreta (13.0% of dose). Due to the slow in vitro metabolism of galunisertib in suspended hepatocytes, a long term hepatocyte system was used to model the human excretion profile.

4.?Expressed cytochromes P450 and hepatocytes indicated clearance was primarily CYP3A4-mediated. Mechanistic static modeling that incorporated small non-CYP-mediated metabolic clearance and renal clearance components predicted an AUC ratio of 4.7 for the effect of itraconazole, a strong CYP3A4 inhibitor, on galunisertib.     

Influence of diabetes mellitus on drug metabolism in man.

Drug metabolizing capacity was assessed in 29 normal subjects and in 28 diabetics on various treatment regimes using the rate of antipyrine elimination as reflux. Plasma half-life of antipyrine was markedly shorter (38%), and the plasma clearance of this drug greater (40%) in diabetics receiving insulin than in controls. There was also an indication of a small increase in rate of test drug elimination in diabetics taking chlorpropamide. Patients being controlled solely on diet or those on tolbutamide did not exhibit an altered rate of drug elimination. The rate of metabolism and inactivation of other drugs may be altered in diabetics taking insulin so that optimal doses of some comcomitantly administered drugs may be different in this group of patients.     

Influence of phenobarbital treatment on cimetidine kinetics

Summary The pharmacokinetics of orally administered cimetidine was studied in 8 healthy subjects before and after 3 weeks of treatment with phenobarbital 100 mg daily, and in a separate study 4 subjects received cimetidine intravenously before and after the administration of phenobarbital. There was no change in the volume of distribution, but total plasma clearance was increased by a mean of 18%, mainly due to a 37% increase in nonrenal clearance. Renal clearance and half-life were not significantly altered. The area under the plasma concentration-time curve after oral administration was significantly (P0.05) reduced by a mean of 15% after phenobarbital treatment. The amount of cimetidine excreted in urine and its sulphoxide metabolite were significantly (P<0.05) reduced, on average by 34% and 26%, respectively by phenobarbital treatment. The data indicate that an apparent 20% reduction in the absorption of cimetidine was due to induction of gastrointestinal metabolism of cimetidine, with some contribution also from hepatic metabolism. Reduced absorption per se could not be totally excluded. Although the magnitude of the change was small, the finding of an 11% decrease in the time to achieve an effective plasma level of cimetidine after phenobarbital treatment may contribute to the ineffectiveness of cimetidine in certain patients.     

Prediction of drug oxidation rates in man: Lack of correlation with serum gamma-glutamyl transpeptidase and urinary excretion of D-glucaric acid and 6β-hydroxycortisol

Summary The plasma half-lives and clearances of antipyrine, phenylbutazone and warfarin, the 24 h urinary excretion of D-glucaric acid and 6-hydroxycortisol, and serum gamma-glutamyl transpeptidase activity were measured in a group of healthy young volunteer subjects who were not taking other drugs. The half-lives of antipyrine and phenylbutazone were positively correlated (r=0.581), and so were the clearances of phenylbutazone and warfarin (r=0.796), but there were no concordances between any of the other test parameters. The results indicate that, in the absence of overt microsomal enzyme induction or inhibition, none of the tests would be of predictive value in the assessment of drug oxidation in clinical practice.Based on a paper presented to the Fifth International Congress of Pharmacology, San Francisco, 24th July 1972     

Plasma concentration of phenylbutazone and its therapeutic effect-studies in patients with rheumatoid arthritis.

1 Phenylbutazone in doses of 50, 100, 200 and 300 mg/day has been given for four periods of 3 weeks to seven patients with rheumatoid arthritis. The trial was double-blind and the order of administration of doses was arranged to eliminate order and carry-over effects. 2 Before the trial and at the end of each period, the patient's responses were assessed by measurement of the duration of morning stiffness, the pain score, paracetamol tablet count, grip strength, digital joint size and articular index. 3 The plasma phenybutazone concentration was measured by gas-liquid chromatography and was also predicted by prior measurement of the phenazone half-life. 4. Compared with the pretreatment period, phenylbutazone had a significant therapeutic effect, as judged by morning stiffness, pain score and articular index, in a dose of 50 mg/day, but no statistically significant differences in effect were seen between the various doses of phenylbutazone. 5 There were no significant coorelations between the plasma concentration of phenylbutazone and any of the clinical assessments. 6 The plasma phenylbutazone concentration agreed closely with that predicted at doses of 50 and 100 mg, but at higher doses the plasma concentration was significantly lower than predicted (P less than 0.05). This may have been due to saturation of the protein binding sites at these doses.     

Effect of repeated exposure to lindane and cadmium on lindane metabolism in rats

The effects of daily administration of cadmium and lindane for 35 days on the metabolism of lindane in rats were investigated. The results indicate that cadmium induces a significant inhibition of lindane metabolism, since the group dosed with lindane plus cadmium had a significantly higher concentration of lindane in plasma and tissues than the group dosed with lindane alone. The inhibition in the metabolic rate of lindane is associated with the cadmium-induced alterations in the disposition of essential trace elements, Zn, Cu and Fe, in the liver.