Sulphation and glucuronidation of paracetamol in human liver: assay conditions.
Explore the source record for details and available documents.
Acetaminophen↗
Biomedical subjects
M L Orme
Publications and source records attributed to M L Orme.
The relative systemic availability of ivermectin after administration as capsule, tablet, and oral solution.
Administration of 12-mg doses of ivermectin (H2B1a) to 12 healthy volunteers in the form of tablets, capsules, and alcoholic oral solution showed the solution to have approximately twice the systemic availability as either of the solid forms, as evidenced both by the maximum concentrations of drug attained in plasma and by the corresponding areas under the plasma concentration vs time curves. However, the two solid formulations showed similar systemic availability.
Administration, Oral↗
Evaluation of Committee on Safety of Medicines yellow card reports on oral contraceptive-drug interactions with anticonvulsants and antibiotics.
1. We have searched the adverse reactions register for the years 1968-84 in an attempt to evaluate data relating to reported pregnancies in women on oral contraceptive steroids (OCS) who concurrently received either an antiepileptic drug or an antibiotic. 2. A total of 43 pregnancies were reported in women on OC therapy who concurrently received antiepileptic drugs and 63 pregnancies in women receiving antibiotics. In addition the number of prescriptions for both antiepileptics and antibiotics in England are reported for the years 1973-84.
Anti-Bacterial Agents↗
Tissue distribution and excretion of amodiaquine in the rat.
14C-Labelled amodiaquine ([14C]AQ) has been administered to male Wistar rats by oral and intravenous routes (n = 6 for each route of administration). Excretion of total 14C-activity was predominantly in the faeces after both oral and intravenous administration. After oral administration 86 +/- 8.3% (mean +/- s.d.) of the 14C administered had been excreted (77 +/- 9% in the faeces, 7 +/- 1% in the urine and 2 +/- 2% in cage washings) over 72 h. Of the 14C administered, 4 +/- 1% was recovered from the tissues, and this was widely distributed, with the main organs of accumulation being kidney, liver, red bone marrow and spleen. After intravenous administration, 102.6 +/- 9.7% of the 14C had been excreted (90.9 +/- 9.6% in faeces, 10.9 +/- 0.8% in urine and 0.5 +/- 0.2% in cage washings) over 72 h. High-performance liquid chromatographic analysis of urine and faeces samples following oral administration of 14C-AQ (8.6 mg kg-1; base) revealed recoveries of 210 +/- 70 micrograms amodiaquine (AQ) and 123 +/- 32 micrograms desethylamodiaquine (AQm) in the faeces, and 2.4 +/- 0.5 micrograms AQ and 18.5 +/- 4.1 micrograms AQm in the urine. Female Wistar rats (n = 6) each received [14C]AQ orally and were killed at the following times: 0.5, 1, 3, 6, 24 and 48 h. Autoradiographs were prepared from each animal and these revealed significant amounts of radioactivity in the tissues at 48 h. This was accumulated maximally by liver and kidney. Radioactivity was detected in bone marrow at 48 h.(ABSTRACT TRUNCATED AT 250 WORDS)
Administration, Oral↗
The disposition of primaquine in the isolated perfused rat liver. Stereoselective formation of the carboxylic acid metabolite.
The disposition of (+) and (-) primaquine (PQ) was studied in the isolated perfused rat liver (IPRL) preparation following a bolus dose (2.0 mg diphosphate salt; N = 6) of each enantiomer. Perfusate plasma concentrations of PQ and the carboxylic acid metabolite (PQm) were determined using previously reported methods. To enable the simultaneous measurement of PQ and PQm in bile a selective and reproducible HPLC assay was developed. Clearance of (-)PQ (8.8 +/- 2.9 ml min-1) was significantly greater than that of (+)PQ (5.5 +/- 1.5 ml min-1) and the apparent volumes of distribution of (-)PQ (606 +/- 182 ml) and (+)PQ (930 +/- 171 ml) were significantly different. Stereoselectivity in the hepatic elimination efficiency was manifest as a significant reduction in half-life (-)PQ 54 +/- 29 min; (+)PQ 123 +/- 33 min) and smaller area under the curve to infinity (-)PQ 254 +/- 96 micrograms ml-1.min, (+)PQ 387 +/- 108 micrograms ml-1.min) for (-)PQ when compared with (+)PQ. A significantly greater peak concentration of PQm was achieved following administration of (-)PQ (0.61 +/- 0.26 micrograms ml-1.min) than (+)PQ (0.19 +/- 0.09 micrograms ml-1). There was no difference between the sum of the areas under the curve to 4 hr for (+) and (-)PQ and the corresponding carboxylic acid metabolite (322 +/- 64 micrograms ml-1 and 317 +/- 75 micrograms ml min-1 respectively). There was no difference in the biliary clearance of (+) and (-)PQ (0.08 +/- 0.02 ml min-1 and 0.14 +/- 0.10 ml min-1 respectively) or the corresponding carboxylic acid metabolites (0.24 +/- 0.13 ml min-1 and 0.29 +/- 0.09 ml min-1). These results strongly suggest stereoselective formation of the carboxylic acid metabolite of primaquine. The significant increase in the volume of distribution of (+)PQ suggests the enantiomer has either an increased affinity for binding sites within the liver and/or erythrocytes or a decreased affinity for circulating perfusate albumin.
Animals↗
Pharmacokinetics of low-dose intravenous pethidine in patients with renal dysfunction.
The kinetics and elimination of pethidine (meperidine) after intravenous administration (150 micrograms/kg) to ten healthy volunteer subjects were compared with those obtained from 18 patients who suffered from varying degrees of renal dysfunction. In both groups of subjects, pethidine was eliminated triexponentially from plasma. However, plasma concentrations in the patients (who were subdivided into patients with severe dysfunction, moderate dysfunction, and mild dysfunction) were consistently higher. The mean +/- SEM elimination half-life (t1/2) of pethidine was significantly longer in the three groups of renal patients: 7.9 +/- 1.1, 20.2 +/- 13.6, 16.6 +/- 5.4, and 14.3 +/- 3.1 hr, respectively, for healthy volunteers, patients with severe, moderate, and mild dysfunction; their mean +/- SEM creatinine clearances were 97.3 +/- 7.5, less than 9.5, 30.0 (3.7), and 63.3 +/- 8.5 mL/min respectively. The mean plasma clearance of the drug was higher in healthy subjects (342.7 +/- 62.5 mL/min) than various groups of renal patients (99.9 +/- 11.6, 120.9 +/- 45.8, and 123.8 +/- 34.1, respectively, for patients with severe, moderate, and mild dysfunction). Impairment of renal function also reduced total plasma protein binding: 58.2 +/- 5.0% in healthy subjects and 31.8 +/- 3.9%, 44.5 +/- 5.0%, and 42.5 +/- 5.6%, respectively, for the three renal patient groups. The percentage of pethidine recovered in the urine was significantly lower in the severe dysfunction group while norpethidine recovery was significantly lower in all three groups of renal patients.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Effect of dose size on amodiaquine pharmacokinetics after oral administration.
Plasma and urine concentrations of amodiaquine (AQ) and desethylamodiaquine (AQm) have been measured after oral administration of AQ 200, 400 and 600 mg in randomised order to 6 healthy subjects. The relationships between AQ dose size and the areas under the plasma concentration vs time curves for AQ and AQm were linear. Likewise there were linear relationships between AQ dose size and the mass of both AQ and AQm excreted in the urine. These data indicate that after oral administration within this dose range AQ displays first-order pharmacokinetics.
Administration, Oral↗
Comparative pharmacokinetics of levonorgestrel and ethinyloestradiol following intravenous, oral and vaginal administration.
The plasma concentrations of levonorgestrel (LNG) and ethinyloestradiol (EE2) have been measured in a random crossover study in five healthy female volunteers given a combination oral contraceptive tablet (250 micrograms LNG and 50 micrograms EE2) by the oral route and per vaginum and also receiving the same dose intravenously. The fractional bioavailability of LNG after oral administration was 1.00 +/- 0.16 (mean +/- S.D.) and after vaginal insertion 0.88 +/- 0.16. The time to peak (tmax) was significantly longer and the peak concentration (Cmax) significantly reduced following vaginal administration. The fractional bioavailability of EE2 after oral dosing was 0.62 +/- 0.11 and after vaginal insertion 0.74 +/- 0.16; tmax was prolonged, hence absorption was slower from the vagina. The reduced rate of absorption was evident in the differences seen in the area under the curve for early time periods for both steroids. However, overall bioavailability is not reduced for either steroid when a single tablet is inserted into the vagina.
Administration, Intravaginal↗
Plasma concentrations of 3-keto-desogestrel after oral administration of desogestrel and intravenous administration of 3-keto-desogestrel.
The plasma concentrations of 3-keto-desogestrel have been measured by radioimmunoassay in a crossover study in nine healthy female volunteers given oral desogestrel (150 micrograms) and ethinyloestradiol (30 micrograms) and intravenous (i.v.) 3-keto-desogestrel (150 micrograms) and ethinyloestradiol (30 micrograms). Bioavailability ranged between 40.0 and 113% with a mean value ( +/- SD) of 76.1 +/- 22.5%. Only 3 subjects had a bioavailability of less than 70%. There was no significant difference in the elimination half life of 3-keto-desogestrel which was 12.6 +/- 4.1h following i.v. administration and 11.9 +/- 4.1h after oral administration of desogestrel.
Administration, Oral↗
The metabolism of 17 alpha-ethinyloestradiol by human liver microsomes: formation of catechol and chemically reactive metabolites.
The metabolism of 17 alpha-ethinyloestradiol (EE2) to catechol and reactive metabolites by human liver microsomes was investigated. 2-Hydroxyethinyloestradiol (2-OHEE2) was either the sole or principal metabolite. Small amounts of 6-hydroxyethinyloestradiol and 16-hydroxyethinyloestradiol were produced by some of the livers. EE2 (10 microM) underwent substantial (5-20% of incubated drug), though highly variable, NADPH-dependent metabolism to material irreversibly bound to microsomal protein. 2-OHEE2 appeared to be the pro-reactive metabolite. The maximum EE2 2-hydroxylase activity was 0.67 nmol min-1 mg-1 microsomal protein, with a Km value of 8.6 microM. Oestradiol, which is mainly hydroxylated to 2-hydroxyoestradiol, was the most potent inhibitor of hydroxylase activity and exhibited competitive inhibition. Progesterone, which undergoes 2-hydroxylation to a minor extent was also a competitive inhibitor, whereas cholesterol and cortisol did not have any appreciable inhibitory effect. Primaquine was the most potent non-steroidal inhibitor but was non-competitive. Other non-steroidal compounds investigated, e.g. antipyrine, did not show any significant effect on EE2 2-hydroxylation. The results of this study suggest that EE2 2-hydroxylation is metabolised by a form(s) of cytochrome P-450 which has affinity for endogenous steroids.
Adolescent↗
Paracetamol interaction with oral contraceptive steroids: increased plasma concentrations of ethinyloestradiol.
The effect of a single dose of paracetamol (1 g) on plasma concentrations of the oral contraceptive steroids ethinyloestradiol (EE2) and levonorgestrel (LNG) has been studied in six healthy female volunteers. The area under the plasma concentration-time curve (AUC0-24) of EE2 was significantly increased following paracetamol administration by 22% (control 2221 +/- 291; following paracetamol, 2702 +/- 452 pg ml-1 h; mean +/- s.d.; P less than or equal to 0.05). The greatest effect was evident in the time period 0-3 h. There was a significant decrease in the AUC of EE2-sulphate after paracetamol (7736 +/- 3791 pg ml-1 h) compared with control (13161 +/- 4535 pg ml-1 h; P less than or equal to 0.05). Plasma concentrations of LNG were unaltered by concurrent paracetamol administration. We conclude that the administration of a single 1 g dose of paracetamol causes an increase in plasma concentrations of EE2 as a result of a reduction in the sulphation of the steroid. This interaction may be of clinical significance in women on oral contraceptive steroids who regularly take paracetamol.
Acetaminophen↗
Intestinal metabolism of ethinyloestradiol and paracetamol in vitro: studies using Ussing chambers.
The intestinal mucosal metabolism of ethinyloestradiol (EE2) and paracetamol (P) has been studied in vitro in Ussing chambers. Histologically normal jejunum or ileum was obtained from 19 patients undergoing various resections. The muscularis externa was stripped off the mucosa and the mucosal sheets mounted between two perspex chambers. Tissue viability was routinely assessed by measurement of the transmural potential difference. The percentage of steroid in the serosal chamber, 2 h after addition of EE2 (2 microCi; 80 ng) to the mucosal chamber was 2.3 +/- 0.8% (mean +/- s.d.) which comprised unconjugated drug (0.4 +/- 0.3%), sulphate conjugates (0.7 +/- 0.5%) and glucuronides (0.9 +/- 0.8%). In the mucosal chamber, 56.6 +/- 11.4% was unconjugated steroid, 33.3 +/- 12.4% sulphate conjugates and 2.1 +/- 2.3% glucuronides. Small amounts of the oxidation products 2-hydroxy and 16-hydroxy-EE2 were present. At 2 h, the percentage of paracetamol in the serosal chamber was 3.2 +/- 1.4% (of added P; 2 microCi; 50 ng) of which 0.5 +/- 0.3% was paracetamol sulphate (PS) and 0.1% was paracetamol glucuronide (PG). In the mucosal chamber 2.4 +/- 0.8% and 1.0 +/- 0.2% was present as PS and PG respectively. The total amount of paracetamol conjugated was approximately 4.0%. When paracetamol in the mucosal chamber was increased to 50 micrograms (i.e. by a factor of 1000) there was a decrease in the percentage of added drug metabolized to PS and an increase in formation of PG. The glucuronide:sulphate ratio was increased from 0.34 to 3.56. Competition for sulphation was evident when both paracetamol and EE2 were presented to the intestinal mucosa.(ABSTRACT TRUNCATED AT 250 WORDS)
Acetaminophen↗
Haemodynamic effects of atenolol, labetalol, pindolol and captopril: a comparison in hypertensive patients with special reference to changes in limb blood flow, heart rate and left ventricular function.
1 To compare the haemodynamic effects of secondary characteristics of beta-adrenoceptor blockers with an angiotensin converting enzyme inhibitor forty patients with previously untreated mild to moderate hypertension were prescribed either atenolol 50-100 mg day-1, labetalol 200-800 mg day-1, pindolol 10-30 mg day-1 or captopril 25-100 mg day-1 and observed for 6 months. 2 Over this period: (a) All four drugs produced similar reductions in blood pressure at rest (P less than or equal to 0.01) and after exercise (P less than or equal to 0.01). (b) All four drugs significantly decreased resting forearm (P less than or equal to 0.01) and calf blood flow (P less than or equal to 0.01). They all also caused a significant reduction in the increased calf blood flow following exercise (P less than or equal to 0.01). (c) No drug produced a change in resting forearm vascular resistance, while resting calf vascular resistance was decreased by captopril and pindolol, unaltered by labetalol and increased by atenolol. Post-exercise calf vascular resistance was increased by atenolol, labetalol and pindolol but unaltered by captopril. (d) Although all four drugs produced a fall in resting heart rate this was significantly greater for atenolol and labetalol (P less than or equal to 0.01). All four treatments however significantly reduced the increase in heart rate following exercise (P less than or equal to 0.01). (e) No drug produced any significant change in resting and post-exercise stroke volume/ejection fraction. 3 It is concluded that despite differing modes of action all four drugs reduce limb blood flow. This primarily appears to be a consequence of reduced perfusion pressure associated with limited autoregulation of skeletal muscle circulation. The reduction in arterial vascular resistance produced by captopril and pindolol is inconsistent and does not appear of major benefit in preserving limb blood flow. The reduction in perfusion with the agents studied may in part be related to a fall in cardiac output associated with decreased heart rate. This suggests that captopril may exert antisympathetic activity when used as an antihypertensive agent.
Adrenergic beta-Antagonists↗
Tolbutamide 4-hydroxylase activity of human liver microsomes: effect of inhibitors.
Eight samples of human liver have been characterised for microsomal protein content, cytochrome P-450 content, tolbutamide 4-hydroxylase and ethinyloestradiol 2-hydroxylase activities. Cytochrome P-450 content correlated significantly with ethinyloestradiol 2-hydroxylase activity but not with tolbutamide 4-hydroxylase activity. There was no significant correlation between ethinyloestradiol 2-hydroxylase and tolbutamide 4-hydroxylase activities. The maximum tolbutamide 4-hydroxylase activity was 0.45 nmol min-1 mg-1 microsomal protein, with a Km value of 74 microM. A number of compounds were tested for their ability to inhibit tolbutamide metabolism. All the compounds showing inhibition were either non-competitive or mixed non-competitive inhibitors of tolbutamide 4-hydroxylation. These studies suggest that tolbutamide is metabolised by an isozyme of cytochrome P-450 which appears to be distinct from those isozymes metabolising many other drugs.
Adolescent↗
Pharmacokinetics of contraceptive steroids in patients with cystic fibrosis.
The pharmacokinetics of the commonly used contraceptive steroids ethinyloestradiol and levonorgestrel were investigated after oral and intravenous administration in six women with cystic fibrosis. The results were compared with data obtained from healthy women of similar age. The total body clearance of ethinyloestradiol was significantly higher in the patients with cystic fibrosis (0.61 (SD 0.19) l/h/kg) than in control women (0.32 (0.16) l/h/kg; p less than 0.02). In addition, the oral bioavailability of ethinyloestradiol was greater in women with cystic fibrosis than in controls (76.9% (11.7%) compared with 47.3% (7.5%); p less than 0.001). As a result of these two changes, the area under the plasma concentration--time curve after an oral dose of ethinyloestradiol was similar in patients and controls. The pharmacokinetics of levonorgestrel did not differ significantly between patients with cystic fibrosis and healthy women. The data suggest that women with cystic fibrosis will receive similar contraceptive protection from these steroids as do healthy women.
Adult↗
Influence of urinary pH on pethidine kinetics in healthy volunteer subjects. 2. A study of ten Chinese subjects.
The pharmacokinetics of intravenous pethidine (150 micrograms kg-1) were determined in 10 healthy Chinese subjects under controlled (acidic and alkaline) and uncontrolled urinary pH. Large variations in the 48 hr urinary recoveries of pethidine and norpethidine were induced by change in urinary pH: (mean +/- S.D.): 24.3 +/- 7.3% & 33.0 +/- 11.4%, 0.4 +/- 0.3% & 3.8 +/- 2.2%, 11.4 +/- 6.9% & 13.9 +/- 2.5%, respectively, under acidic, alkaline and uncontrolled urinary pH for pethidine and norpethidine. There was no significant difference in the terminal half-lives, t 1/2 (6.1 to 7.0 hr) of pethidine, although the area under the plasma concentration-time curve under acidic urinary conditions was slightly lower and renal clearance of the drug higher than those under alkaline and uncontrolled urinary conditions. Confirming previous results from Caucasian subjects, under all 3 conditions pethidine disappeared from the plasma tri-exponentially and acidification of the urine may increase body clearance of unchanged pethidine due mainly to greater renal clearance of the drug; this may be useful clinically to treat acute pethidine poisoning. However, under acidic urinary conditions, Chinese subjects excreted more norpethidine than Caucasians (33.0 +/- 11.4% and 23.4 +/- 4.6%, respectively).
Adult↗
Disposition of pethidine in man under acidic urinary pH. 3. A comparison of pharmacokinetics among Caucasian, Chinese and Indian subjects.
The pharmacokinetics of low dose pethidine (150 micrograms kg-1) after intravenous administration were determined in 10 Caucasian, 10 Chinese and 10 Indian healthy volunteers under conditions of acidic urinary pH. Plasma and urine concentrations of pethidine and norpethidine were measured by gas liquid chromatography. In all 3 ethnic groups, the disappearance of pethidine from plasma was best described by a tri-exponential function. No significant differences were observed in the elimination half life, renal clearance and total plasma clearance of the drug. The significantly lower AUC and higher (approaching significance) apparent volume of distribution in the 2 Asian groups may be explained in terms of more readily distribution of the drug (significantly higher K21 rate constants were obtained from both Chinese and Indian subjects according to a 3-compartment open model) due possibly to more frequent movement of these subjects during the early part of experiment. More norpethidine was recovered in the urine of the Chinese and Indian subjects; this may suggest an interethnic difference in the oxidative demethylation of pethidine.
Adult↗
Non-steroidal anti-inflammatory drugs and the kidney.
Explore the source record for details and available documents.
Acute Kidney Injury↗