Plasma Paracetamol Levels Research Articles

Two-bag intravenous N-acetylcysteine, antihistamine pretreatment and high plasma paracetamol levels are associated with a lower incidence of anaphylactoid reactions to N-acetylcysteine

Context: N-acetylcysteine (NAC) is used worldwide to prevent liver injury after paracetamol overdoses. Anaphylactoid reactions to NAC occur frequently and often lead to treatment interruptions or discontinuations. In Denmark in 2013, the NAC treatment regimen was simplified from a three-bag to a two-bag NAC regimen. Factors of importance for the development of anaphylactoid reaction to this new regimen are poorly explored. Previous studies have suggested a protective effect of high plasma levels of paracetamol on the development of anaphylactoid reactions. Likewise, exposure to antihistamines prior to NAC treatment may protect against these reactions.Methods: This is a retrospective cohort study of patients treated with NAC and with at least one plasma paracetamol sample performed in the Capital Region of Denmark from 2010 to 2017. The primary outcome was the incidence of anaphylactoid reactions to NAC requiring intravenous treatment with antihistamines and/or glucocorticoids. Logistic regression analyses were carried out to identify the risk of developing an anaphylactoid reaction to NAC affected by influencing factors.Results: Of 4315 admissions included in the study, 259 (6.0%) developed an anaphylactoid reaction to NAC. The two-bag regimen (adjusted OR 0.44 [95%CI: 0.32–0.60]), increasing age (adjusted OR 0.84 [95%CI: 0.78–0.90] per 10-year increase) or children <10 years (adjusted OR 0.14 [95%CI: 0.04–0.36]) and antihistamine co-ingestion in overdose (adjusted OR 0.17 [95%CI: 0.02–0.64]) were associated with significantly fewer anaphylactoid reactions. High plasma paracetamol concentrations protected against development of anaphylactoid reactions during the two-bag regimen (adjusted OR 0.59 [95%CI: 0.47–0.71] and three-bag regimen 0.82 [95%CI: 0.72–0.94] per doubling of paracetamol concentration). The effect differed between the two regimens (p = .004 for interaction).Conclusion: In this retrospective cohort, a high peak plasma paracetamol concentration, age, antihistamine co-ingestion and use of the two-bag NAC regimen were associated with fewer anaphylactoid reactions to NAC.

Retrospective study of paracetamol poisoning in children aged zero to six years found no cases of liver injury.

This study focused on children aged zero to six years with suspected single-dose paracetamol poisoning, which has not been investigated in Denmark. We evaluated the incidence of liver injuries and the use of activated charcoal and N-acetylcysteine treatment. Our retrospective study was performed in three paediatric hospital centres from 2001 to 2012. Data on symptoms, time of ingestion, blood biochemistry, treatment and adverse reactions were collected. The results were evaluated against the Rumack-Matthew nomogram. We identified 221 children (58% male), with a mean age of 2.67 ± 1.05 years. Activated charcoal treatment was given in 87% of cases, but only 15% of the children received treatment within one hour of the suspected paracetamol poisoning. Although 80% of the children received N-acetylcysteine treatment, only one case (0.5%) had a toxic plasma paracetamol level according to the treatment nomogram. Abdominal pain or vomiting was associated with higher paracetamol levels in plasma. None of the children developed liver injuries. We found a low incidence of significant poisoning and liberal use of N-acetylcysteine and activated charcoal treatment in Danish children aged zero to six years with suspected paracetamol poisoning. Vomiting or abdominal pain was associated with elevated plasma paracetamol levels. No liver injuries were reported.

Interventions for paracetamol (acetaminophen) overdose.

Interventions for paracetamol (acetaminophen) overdose.

Caracterización de la ingestión por sobredosis de paracetamol: Reporte de un centro de información toxicológica chileno

Paracetamol (acetaminophen) is an analgesic and antipyretic drug widely used across the world. Its ingestion is one of the most common causes of drug overdose. In the United States is the first cause of acute hepatitis in adults. To describe the epidemiological profile of paracetamol overdose in Chile. Cross sectional retrospective study that included all the phone call inquiries received at the Poison Control Center of the Pontificia Universidad Catolica de Chile (CITUC) during 2009. Nine hundred fifty nine inquiries involving acute paracetamol exposures were received. Women represented a 63.1% of the cases. Half of the cases were suicide attempts, of which 74.8% were women. Accidental exposures occurred mainly in children. In 29.3% of the patients, the exposure was considered to involve a hepatotoxic dose. Women had 2.7 times the risk of men to ingest a toxic dose of paracetamol with suicidal purpose (Odds ratio (OR) = 2.7; 95% confidence interval (Cl): 2.1-3.6; p < 0.001). Adolescents had 3.4 times the risk of the general consultants (OR: 3.4; 95% Cl: 2.4-4.7; p < 0.001). Paracetamol overdose is common in Chile. Authorities should carry out preventive measures. Antidotes and the capacity to measure plasma levels of paracetamol should be available in healthcare centers.

Oral liquid in situ gelling methylcellulose/alginate formulations for sustained drug delivery to dysphagic patients

Background: Elderly patients with swallowing dysfunction may benefit from the oral administration of liquid dosage forms with in situ gelling properties.Aim: We have designed in situ gelling liquid dosage formulations composed of mixtures of methylcellulose, which has thermally reversible gelation properties and sodium alginate, the gelation of which is ion-responsive, with suitable rheological characteristics for ease of administration to dysphagic patients and suitable integrity in the stomach to achieve a sustained release of drug.Method: The rheological and gelation characteristics of solutions containing methylcellulose (2.0%) and sodium alginate (0.25–1.0%) were assessed for their suitability for administration to dysphagic patients. The gel strength and in vitro and in vivo release characteristics of gels formed by selected formulations were compared using paracetamol as a model drug.Results: Mixtures of 2.0% methylcellulose and 0.5% alginate containing 20% d-sorbitol were of suitable viscosity for ease of swallowing by dysphagic patients and formed gels at temperatures between ambient and body temperature allowing administration in liquid form and in situ gelation in the stomach. In vitro release of paracetamol from 2.0% methylcellulose/0.5% alginate gels was diffusion-controlled at pH 1.2 and 6.8. Measurement of plasma levels of paracetamol after oral administration to rats of a 2.0% methylcellulose/0.5% alginate formulation showed improved sustained release compared to that from 2.0% methylcellulose and 0.5% alginate solutions and from an aqueous solution of paracetamol.Conclusions: Solutions of mixtures of methylcellulose and alginate in appropriate proportions are of suitable consistency for administration to dysphagic patients and form gels in situ with sustained release characteristics.

Postoperative Plasma Paracetamol Levels following Oral or Intravenous Paracetamol Administration: A Double-Blind Randomised Controlled Trial

In day-case surgery paracetamol is commonly given orally preoperatively, or intravenously intraoperatively. In this double-blind randomised controlled trial we investigated which of these methods of administration achieved therapeutic plasma levels most effectively in the early postoperative period. Thirty patients undergoing day case arthroscopy of the knee were randomised to receive either 1.0 g oral paracetamol 30 to 60 minutes preoperatively (20 patients) or 1.0 g intravenous paracetamol intraoperatively (10 patients). Plasma paracetamol levels were measured 30 minutes after arrival in the recovery room. Secondary outcomes included postoperative pain scores, rescue analgesia requirements and duration of stay in the recovery room. All patients receiving the intravenous preparation had plasma levels above the analgesic level compared to less than half (7/20) in the oral group. Mean plasma paracetamol levels were 88.6 µmol/l for the intravenous group and 53.2 µmol/l for the oral group (P=0.0005). There were trends towards reduced rescue analgesia and duration of stay in the recovery room for the intravenous group although not reaching statistical significance. There was no difference in pain scores between groups. Intraoperative administration of 1.0 g of intravenous paracetamol more reliably achieved effective paracetamol levels in the early postoperative period compared to an equal dose given orally preoperatively. Only a minority of patients receiving the 1.0 g oral dose preoperatively had plasma levels in the therapeutic analgesic range.

Relationship between paracetamol plasma levels and its analgesic effect in the rat.

The relationship between plasma levels of paracetamol and its analgesic effect was studied in the rat using a model of pain-induced functional impairment (PIFI). Female Wistar rats received an intraarticular injection of 30% uric acid in the knee of the right hind limb, inducing its dysfunction. Animals then received oral paracetamol at doses of 178, 316 or 562 mg kg-1 and the recovery of functionality over time was considered as an expression of analgesia. Paracetamol plasma levels were determined by HPLC. Results showed that there is a direct relationship between paracetamol plasma levels and its analgesic effect that follows a sigmoidal model according to the Hill equation. The PIFI model appears to be a useful tool to establish pharmacokinetic/pharmacodynamic relationships for non-narcotic analgesics.

Characterization of the analgesic effect of paracetamol and caffeine combinations in the pain-induced functional impairment model in the rat.

The analgesic activities of paracetamol (100, 178, 316 and 562 mg kg-1), caffeine (10, 18, 32 and 56 mg kg-1) and combinations of these doses were tested on a pain-induced functional impairment model in the rat. Dysfunction of the right hind limb was induced by an intra-articular injection of 30% uric acid in the knee. Drugs were given orally and the recovery of functionality over time was considered as an expression of analgesia. Paracetamol alone induced a dose-dependent analgesic effect whereas caffeine alone did not show any activity at the assayed doses. Combinations of 316 mg kg-1 paracetamol with either 10, 18, 32 or 56 mg kg-1 caffeine yielded analgesic effects significantly greater than that of paracetamol alone. The highest potentiation was observed with a paracetamol-caffeine mixture of 316-32 mg kg-1. Caffeine coadministration, however, did not significantly change paracetamol plasma levels. No potentiation was obtained with other combinations. Paracetamol plasma levels and analgesic effect observed with administration of 316 mg kg-1 paracetamol alone or 316-32 mg kg-1 of paracetamol-caffeine were fitted to the sigmoidal Emax model according to the Hill equation. The curves obtained were parallel, but that of the combination was shifted to the left. It is concluded that caffeine is able to potentiate the analgesic effect of paracetamol by a pharmacodynamic mechanism, but this only occurs at certain dose combinations.

In situ gelling formulation based on methylcellulose/pectin system for oral-sustained drug delivery to dysphagic patients

Background: Oral-sustained release gel formulations with suitable rheological properties have been proposed as a means of improving the compliance of dysphagic and geriatric patients who have difficulties with handling and swallowing oral dosage forms. Aim: We have modified the rheological and release properties of thermally reversible methylcellulose solutions by admixture with pectin, the gelation of which is ion-responsive, with the aim of formulating an in situ gelling vehicle suitable for oral-sustained drug delivery. Method: Gels formed by solutions containing methylcellulose (1.0–2.0%) and pectin (0.5–2.0%) were assessed for suitable gel strength, and in vitro and in vivo release of paracetamol. Results: Addition of 1.5% pectin to a 2.0% methylcellulose formulation containing 20% d-sorbitol and calcium ions in complexed form increased the gel strength and provided a formulation with a suitable viscosity for ease of swallowing by dysphagic patients. Gels formed in situ after oral administration of this formulation retained their integrity in the rat stomach for sufficient time for sustained release to be achieved. In vitro release of paracetamol from methylcellulose, pectin, and methylcellulose/pectin gels was diffusion-controlled. Plasma levels of paracetamol after oral administration to rats (gastric pH 2.6 and 5.5) of a solution including 2.0% methylcellulose/1.5% pectin showed improved sustained release compared with that from both 2.0% methylcellulose and 1.5% pectin solutions. Conclusions: The addition of suitable concentrations of pectin to methylcellulose solutions produces in situ gelling formulations with suitable viscosity for administration to dysphagic patients and improved sustained release characteristics.

In situ gelling xyloglucan/alginate liquid formulation for oral sustained drug delivery to dysphagic patients

Background: The oral administration of liquid dosage forms of suitable consistency and with sustained release characteristics may provide a means of improving the compliance of geriatric patients who experience difficulties in swallowing conventional solid dosage forms. Aim: We have designed and evaluated liquid preparations for administration to dysphagic patients, composed of aqueous mixtures of xyloglucan, which has thermally reversible gelation characteristics, and sodium alginate, which has ion-responsive gelation characteristics. Method: The gelation and in vitro and in vivo release characteristics of liquid formulations containing appropriate concentrations of xyloglucan and sodium alginate with mannuronate/guluronate ratios of either 0.5 or 0.8 were assessed. Results: Aqueous mixtures of 1.5% xyloglucan and 0.5% alginate had suitable viscosities for ease of swallowing and appropriate gelation temperatures (∼33°C) to ensure in situ gelation following oral administration. The in vitro release of paracetamol at pH 5.0 from gels formed by these formulations and also by a 1.5% xyloglucan solution was diffusion-controlled. Plasma levels of paracetamol after oral administration to gastric-acidity controlled rats (pH 5) of a solution containing 1.5% xyloglucan/0.5% alginate showed that a more sustained release was achieved from the gels formed by the in situ gelation of this formulation compared with that of a 1.5% xyloglucan solution. Visual observation of the contents of the rat stomach after oral administration showed that the inclusion of alginate in the xyloglucan solutions was effective in reducing gel erosion, so sustaining drug release. Conclusions: Liquid formulations of xyloglucan and sodium alginate in appropriate proportions are of suitable consistency for ease of administration to dysphagic patients and form gels in situ in the rat stomach capable of sustaining the release of paracetamol over a 6-hour period.

Overdose of methyldopa, indapamide and theophylline resulting in prolonged hypotension, marked diuresis and hypokalaemia in an elderly patient

An 89-year-old man with a history of hypertension, chronic obstructive pulmonary disease, personality disorder and previous attempts of self-poisoning attempted suicide by swallowing two mouthfuls of tablets (methyldopa 250 mg, theophylline SR 200 mg, indapamide 2.5 mg and paracetamol 500 mg). He had prolonged, severe hypotension, necessitating the use of 3000 ml of Gelofusine and almost 2 days of intravenous norepinephrine infusion. He had marked diuresis for 4.5 days, requiring continuous and bolus infusions of intravenous fluids. He had marked renal potassium loss, requiring vigorous potassium replacement therapy. Multiple-dose activated charcoal was used to enhance theophylline elimination. The plasma paracetamol level was below the treatment line. Methyldopa via its metabolite stimulates postsynaptic alpha-adrenergic receptors in cardiovascular control centres in the brain, causing a reduction in peripheral sympathetic tone and a fall in arterial blood pressure and heart rate. In overdose, it causes hypotension, bradycardia and drowsiness. The natriuretic, kaliuretic and vasodilatory effects of indapamide are exaggerated in overdose, resulting in diuresis, hypokalaemia and hypotension. Theophylline markedly increases the level of circulating catecholamines, which stimulate the vascular beta(2)-adrenergic receptors with decreased peripheral vascular resistance. Peripheral vasodilation and hypotension occur in significant theophylline poisoning. Intracellular shift of potassium results in hypokalaemia. The prescribing physicians should recognise elderly patients at a high risk of self-poisoning and avoid using drugs with a high toxicity in overdose (e.g. theophylline and methyldopa). Restricting access to hazardous drugs (in overdose) would be of paramount importance to reduce the number of severe acute poisoning cases and case-fatalities.

Influence of fruit drinks with or without lactobacillus Lp299v on the gastrointestinal uptake of paracetamol in man

BackgroundClinical observations have revealed that patients throw up undigested paracetamol tablets several hours following intake of rosehip drink with Lp299v (Proviva). The purpose of this study was to demonstrate if this translates into altered plasma levels of paracetamol in nineteen healthy subjects consuming 200 ml of water, Rose hip drink or Proviva together with 1.5 gram of paracetamol.FindingsThe concentration of paracetamol in plasma increased rapidly when the paracetamol-containing tablets were consumed together with water and after 30 minutes a median level of 90 μmol/l was reached (a 95% confidence interval of 57,161). The corresponding 30 minutes values of paracetamol levels in the presence of rosehip with or without Lp299v were 0 μmol/l (95% confidence intervals contain only zero for both rosehip treatments). There were significant differences in AUC, maximal paracetamol concentration and in time to maximal paracetamol concentration. The median maximal paracetamol concentration was 147 μmol/l for water, which is significantly higher than the median for rosehip drink with Lp299v,113.5 μmol/l, and than the median for rosehip-drink without Lp299v, 106.5 μmol/l (p = 0.002, and p = 0.003); there were no significant difference between rosehip drink with or without Lp299v (p > 0.3).ConclusionWe have demonstrated an interaction between the uptake of paracetamol and the solvent in rosehip drink/Provia which mainly consists of long chain carbohydrates. This may in the clinic translate to the use of more drug than it is necessary.

Bioavailability and Metabolism of Orange Juice Flavanones in Humans: Impact of a Full-Fat Yogurt

The bioavailability of dietary phytochemicals may be influenced by the food matrix in which they are consumed. In this study the impact of a full-fat yogurt on the bioavailability and metabolism of orange juice flavanones was investigated. Human plasma and urine were collected over a 24 h period after the consumption of 250 mL of orange juice containing a total of 168 micromol of hesperetin-7-O-rutinoside and 12 micromol of naringenin-7-O-rutinoside, with and without 150 mL of full-fat yogurt. The juice also contained 1 g of paracetamol and 5 g of lactulose. HPLC-MS(2) analysis revealed the accumulation of hesperetin-7-O-glucuronide, and an unassigned hesperetin-O-glucuronide metabolite in plasma reached a peak concentration (C(max)) of 924 +/- 224 nmol/L, 4.4 +/- 0.5 h (T(max)) after orange juice ingestion. The T(max) is indicative of absorption in the colon. When the juice was consumed with yogurt, neither the C(max) at 661 +/- 170 nmol/L nor the T(max) at 5.1 +/- 0.4 h were significantly different from those obtained with juice alone. The two hesperetin glucuronides were also excreted in urine along with a third hesperetin-O-glucuronide, two hesperetin-O-glucuronide-O-sulfates, a hesperetin-O-diglucuronide, a naringenin-O-diglucuronide, and, tentatively identified, naringenin-7-O-glucuronide and naringenin-4'-O-glucuronide. This indicates the occurrence of substantial, postabsorption, phase II metabolism prior to urinary excretion. The quantity of flavanone metabolites excreted 0-5 h after orange juice ingestion was significantly reduced by yogurt, but over the full 0-24 h urine collection period, the amounts excreted, corresponding to ca. 7.0% of intake, were not affected by the addition of yogurt to the drink. Nor did yogurt have a significant effect on gastric emptying, as determined by plasma paracetamol levels, or on the mouth to cecum transit time of the head of the meal, assessed by measurement of lactulose-derived breath hydrogen. There is also a discussion of the merits of studies of the absorption and metabolism of flavanones based on direct analysis of metabolites by HPLC-MS and the more traditional indirect approach where samples are treated with a mollusc glucuronidase/sulfatase preparation prior to HPLC analysis of the released aglycones.

In situ gelling xyloglucan/pectin formulations for oral sustained drug delivery

This study has examined the gelation and release characteristics of mixtures of xyloglucan, which has thermally reversible gelation characteristics, and pectin, the gelation of which is ion responsive, with the aim of formulating an in situ gelling vehicle suitable for oral sustained drug delivery. An investigation of the effect of the inclusion of pectin (0.75% (w/w)) on the rheological properties of gels formed from solutions of xyloglucan (1.5 and 2.0% (w/w)) showed a significantly greater gel strength when pectin was present in the formulation. The in vitro release of paracetamol from gels containing 1.5% (w/w) xyloglucan, and 1.5 or 2.0% (w/w) xyloglucan/0.75% (w/w) pectin was diffusion-controlled. Measurement of plasma levels of paracetamol after oral administration to rats of a solution containing 1.5% (w/w) xyloglucan and 0.75% (w/w) pectin showed that a more sustained release and higher drug bioavailability was achieved from the gels formed by the in situ gelation of this formulation compared to that of a 1.5% (w/w) xyloglucan solution; 0.75% (w/w) solutions of pectin did not form gels under these conditions. Visual observation of the contents of the rat stomach at intervals after oral administration showed that the inclusion of pectin in the xyloglucan solutions was effective in reducing gel erosion, so sustaining drug release.

Correlation of paired plasma and saliva paracetamol levels following deliberate self-poisoning with paracetamol (The Salivary Paracetamol In Toxicology [SPIT] study)

Aim. To determine the correlation between plasma and saliva paracetamol levels following paracetamol deliberate self-poisoning. Methods. Paired plasma and saliva paracetamol levels were measured. Saliva analysis was performed contemporaneously using a colorimetric method. Results. 21 patients (76% female) mean age 28.3 ± 12.9 years (range 15–55) were enrolled. Mean reported paracetamol ingestion was 10.3 g (range 2–20 g). Specimens were collected at a mean of 6.2 ± 3.1 hours post-ingestion (range 4–13 hours) and mean plasma and saliva paracetamol levels were 48 mg/L and 62 mg/L respectively (mean difference 14; 95% CI 5–22; p < 0.004); Pearson's correlation r = 0.95 (p < 0.0001). No patient needing treatment would have been missed using saliva levels only. Conclusion. There is concordance between the indications for treatment of paracetamol deliberate self-poisoning based on plasma and saliva paracetamol levels. Saliva paracetamol levels are typically higher than plasma levels. Further studies involving larger numbers of patients, comparing plasma and saliva paracetamol levels in patients with potentially toxic plasma paracetamol concentrations, would be useful in determining the potential clinical value of this method.

A pharmacokinetic study of paracetamol in Thai β-thalassemia/HbE patients

Thalassemia may alter the pharmacokinetics of several drugs in thalassemic patients. Paracetamol is a commonly used analgesic and antipyretic drug which is extensively metabolized in the liver via glucuronidation. The aim of this study was to compare the pharmacokinetics of paracetamol (PCM) and its metabolites [paracetamol glucuronide (PCM-G), paracetamol sulfate (PCM-S), and paracetamol cysteine (PCM-C)] in 16 patients with 16 normal subjects. Following an overnight fast, a single dose of paracetamol (1,000 mg of Tylenol(R)) was given and blood samples were obtained at predose, 0.5, 1, 1.5, 2, 3, 4, 5, 7, and 9 h after dosing for determination of the plasma levels of PCM and its metabolites by high-performance liquid chromatography. There was no significant difference in maximum concentration of PCM between groups. However, a significantly shorter elimination half-life of PCM was observed in the thalassemic subjects (p<0.001). Total apparent clearance of PCM was significantly faster in thalassemic subjects (p<0.01) while the apparent volume of distribution of PCM did not change. The area under the concentration time curve (AUC(0->infinity)) of PCM-G and PCM-S increased in thalassemic subjects (p<0.05) whereas this parameter for PCM-C was slightly lower in the patients. The half-lives of PCM metabolites were significantly shorter (p<0.01) in thalassemic subjects. The results indicate that the elimination of PCM and its metabolites in thalassemic subjects is faster than that in normal subjects. Our pharmacokinetic data provide additional evidence that plasma PCM-G is higher in thalassemic patients with hyperbilirubinemia, which could be a casual relationship in regulating the UDP-glucuronosyltransferase expression.

ECG Abnormalities in Co-proxamol (Paracetamol/Dextropropoxyphene) Poisoning

Objectives. 1) To investigate ECG changes following co-proxamol (paracetamol 325 mg and dextropropoxyphene 32.5 mg) overdose in comparison to co-codamol (paracetamol and codeine) or co-dydramol (paracetamol and dihydrocodeine) in a prospective study. 2) To examine the relationship between estimated dextropropoxyphene dose and ECG changes in a larger patient population. Background. Co-proxamol is a common cause of drug-induced death and hospital admission in the United Kingdom. ECG changes following dextropropoxyphene have been reported in animals and man, including QRS prolongation. Methods. The prospective study was conducted on 15 patients and controls with overdose. A retrospective study of a cohort of 159 co-proxamol overdoses from a combined data set from Edinburgh and Newcastle, Australia was also conducted. The measured or estimated “four hour” plasma paracetamol level was used as a surrogate of the amount of dextropropoxyphene ingested. Results. In the prospective study co-proxamol overdose caused statistically significant QRS prolongation (mean [95% CI] 99.36 [96.19, 102.53] msec), compared to the other combination opioid-paracetamol products (82.84 [80.81, 84.88] msec) but no effect on PR or QTc. QRS duration increase was evident soon after exposure and remained prolonged and stable over the following 24 h. In the retrospective cohort study a dose dependency of effect on QRS was documented, although the correlation coefficient relating paracetamol level to effect was relatively weak (r = 0.338, Sig. [2-tailed] 0.003, n = 74). Conclusions. QRS is significantly prolonged in co-proxamol overdose, and this prolongation is dose dependent. These findings have clinical relevance to the management of patients with co-proxamol poisoning.

Diagnostic clues from elevated plasma paracetamol levels

Diagnostic clues from elevated plasma paracetamol levels

Diagnostic clues from elevated plasma paracetamol levels

Diagnostic clues from elevated plasma paracetamol levels

Effect of active and passive cigarette smoking on CYP1A2-mediated phenacetin disposition in Chinese subjects.

The effect of active and passive cigarette smoking on CYP1A2-mediated phenacetin disposition was evaluated in a controlled study of 36 healthy Chinese subjects. Each subject was administered a single oral dose of phenacetin (900 mg), and frequent blood samples were taken for up to 12 hours for simultaneous high-pressure liquid chromatography determinations of plasma concentrations of phenacetin and metabolically derived paracetamol. Compared with values observed in controls not exposed to cigarette smoking, subjects who smoked 7 to 40 (median, 20) cigarettes per day exhibited a 2.5-fold higher phenacetin apparent oral clearance (7.2, 4.3-12.0 L x h(-1) x kg(-1) vs 2.9, 1.8-4.6 L x h(-1) x kg(-1) [geometric means, 95% confidence intervals]; n = 12, p < 0.05). In subjects exposed to passive smoking, phenacetin's apparent oral clearance (3.6, 2.0-46.6 L x h(-1) x kg(-1), n = 12) was intermediate between the values observed in the two other groups. Plasma paracetamol levels were moderately lower in active smokers than in passive smokers and controls. These results demonstrated that, in contrast to results found in previous studies, Chinese subjects were fully susceptible to the inducing effect of cigarette smoke on CYP1A2 activity.