Effect of carbamazepine on psychomotor performance in näive subjects

Summary The effect of a single dose of carbamazepine (CBZ), 10 mg kg^–1, on a battery of simple psychomotor tests was investigated in 12 healthy subjects (6 male, 6 female) in a balanced randomised double blind placebo controlled cross-over study. Psychomotor testing and blood sampling for total and free plasma CBZ, and CBZ 10, 11 epoxide concentration were performed at 10, 12, 14, 16, 18 and 34 h after oral dosing (23.00 h the previous evening). CBZ impaired i) critical flicker fusion threshold frequency at all time points up to 18 h (p<0.005); ii) total choice reaction time at 10 h (p<0.005) and 18 h (p<0.008); iii) card sorting at 14 h (p<0.001).No significant effect on finger tapping was noted. Subjects adjudged themselves more sedated on CBZ as compared to placebo at 12, 14 and 16 h (p<0.008). Plasma total and free CBZ concentrations (mean ± SD) peaked at 10 h (8.8±0.2 mg l^–1) and 16 h (1.88±0.3 mg l^–1) after dosing respectively. CBZ 10, 11 epoxide values were all less than 10% of total CBZ concentrations and, therefore, were unlikely to contribute to the pharmacodynamic effect. Total choice reaction time was significantly more impaired in females (p<0.05) but no sex difference occurred with the other tests or CBZ concentrations at any time point. No significant correlations were found between individual total or free CBZ concentrations and corresponding test performances at each time point. This study has demonstrated impairment of psychomotor function following CBZ in healthy subjects using a series of simply performed tests. This approach can now be applied to patients with epilepsy receiving long-term treatment with CBZ and other anticonvulsants.     

Influence of mild thyroid dysfunction on antipyrine clearance and metabolite formation in man

Summary The salivary kinetics and rates of metabolite formation of antipyrine were studied in 6 hyperthyroid and 6 hypothyroid out-patients on 2 occasions, on admission and when T3 and T4 levels had returned to normal after treatment with carbimazole (hyperthyroidism) or l-thyroxine (hyperthyroidism). In hyperthyroidism the half-life of antipyrine was significantly shorter (p<0.05) than after recovery (9.3±1.0 versus 10.6±0.9 h). Hypothyroid patients showed a significantly longer elimination half-life before treatment than after recovery (12.7±2.6 versus 10.3±2.6 h). Antipyrine clearance in hyperthyroid patients was decreased after treatment from 2.7±0.3 to 2.4±0.3 l/h, and it was increased in hypothyroid patients from 2.1±0.4 to 2.5±0.5 l/h (p<0.05). The changes in clearances for the production of the antipyrine metabolites 4-hydroxyantipyrine (OHA), norantipyrine (NORA) and 3-hydroxy-methylantipyrine (HMA) were of the same order of magnitude as total antipyrine clearance, and no selectivity towards any of the metabolic pathways of antipyrine was apparent. Mild thyroid dysfunction seems to affect oxidative drug metabolizing enzyme activity in a non-selective manner and only to a small extent (10–30%). It is suggested that adjustment of the therapeutic regimens of various drugs in mild thyroid disease will only rarely by required on the basis of pharmacokinetic considerations.     

Chronopharmacokinetics of theophylline after sustained release and intravenous administration to adults

Summary The influence of time of drug administration on pharmacokinetics of theophylline was studied both after ingestion of a sustained-release tablet, containing choline theophyllinate (Zy 15061-S. R.; Teovent^®; Sabidal^®; ZYMA S.A.) and after intravenous infusion of aminophylline to eight healthy volunteers. Both drugs were administered in the morning (10 a.m.) and on a separate occasion in the evening (10 p.m.) after a 12 h period of fasting.After oral administration of a dose of 540 mg theophylline, the drug was steadily absorbed, both during day-time and during night-time. In some subjects absorption was slower in the evening. Maximum theophylline plasma concentrations were reached after 3.3±0.4 h (mean±SD) and 3.9±1.4 h respectively (not significantly differentp>0.05).The maximum plasma concentrations were almost identical after administration in the morning and in the evening (12.6±3.3 mg·l^–1 and 13.1±1.4 mg·l^–1 respectively).There was also no significant difference (p>0.05) between the areas under the plasma concentration-time curves after oral and intravenous administration, both at day-time and at night-time. This finding indicates complete bioavailability of the sustained release tablets on both occasions.After administration of the tablets in the morning the plasma concentration 12 h post dosing was significantly lower than after administration in the evening: c ₁₂ ¹ accounted for 6.0±2.0 mg·l^–1 after intake at 10 a.m. and for 7.9±2.1 mg·l^–1 after ingestion at 10 p.m. (p<0.01).A similar observation was done after intravenous administration of the drug: c₁₂ was 6.6±1.6 mg·l^–1 after starting the infusion in the morning and 8.0±1.8 mg·l^–1 after infusing the drug in the evening (p<0.01). This phenomenon could be explained by the finding of a significantly prolonged half-life of theophylline during night-time, provided that the plasma concentrations were in the range of 5 to 15 mg·l^–1 (which coincides approximately with the therapeutic range of the drug). For day-time elimination the half-life of theophylline was found to be 6.2±0.9 h and for night-time elimination 8.0±2.0 h (p<0.01), which means an increase of 29.6±20.9% during the night. The prolonged half-life of theophylline at night-time might be of therapeutic benefit in preventing bronchus obstruction in the morning.     

Pharmacokinetics of bacmecillinam and pivmecillinam in volunteers

Summary The pharmacokinetics of bacmecillinam and pivmecillinam were studied in healthy fasting volunteers given tablets in a cross-over, randomized order. The mean (±SD) peak levels of plasma mecillinam were 1.43±0.34, 2.73±0.43, and 4.62±1.41 mg/l after bacmecillinam 100, 200, and 400 mg and 2.38±0.65 mg/l after pivmecillinam 400 mg. The corresponding areas under plasma Vs time curves (AUC) were 2.21±0.19, 3.99±0.63, and 7.74±1.38 mg·h·l^–1 for bacmecillinam and 5.35±0.93 mg·h·l^–1 for pivmecillinam. The elimination half-lives were 0.8–1.1h for bacmecillinam and 0.7h for pivmecillinam. The 12 h urinary recovery of unchanged mecillinam after the 400 mg doses was 41% for bacmecillinam and 30% for pivmecillinam. The 400 mg dose of bacmecillinam gave a significantly higher plasma peak (p<0.001), AUC (p<0.001) and urinary recovery (p<0.001) than did pivmecillinam 400 mg. The plasma peaks appeared earlier and the rate of absorption was higher after bacmecillinam than after pivmecillinam (p<0.05). In conclusion, bacmecillinam had a better bioavailability than pivmecillinam in the tablet formulations studied. The AUC increased linearly with increasing doses of bacmecillinam.     

Changes in circulating androgens during short term carbamazepine therapy.

Serum concentrations of testosterone, androstenedione, dehydroepiandrosterone sulphate (DHAS), sex hormone binding globulin (SHBG) and luteinising hormone (LH) were measured before, during and after 21 days treatment with carbamazepine (CBZ)400 mg daily in six healthy male subjects. Induction of hepatic microsomal enzyme activity was confirmed by an increase in antipyrine clearance (P less than 0.02) and a fall in circulating CBZ concentrations from the seventh to the fourteenth CBZ dose (P less than 0.05). Within 7 days of starting CBZ there was a rise in SHBG (P less than 0.05) and a fall in testosterone, free testosterone fraction, DHAS and androstenedione (P less than 0.05). Testosterone, free testosterone fraction and androstenedione levels rose towards baseline by the end of the treatment period while DHAS concentration remained low (P less than 0.05). The rise in SHBG and increased androgen catabolism is most likely to be secondary to induction of hepatic monooxygenase activity by CBZ. These changes may be implicated in the production of sexual dysfunction encountered in some epileptic patients on chronic anticonvulsant therapy.     

Effects of simvastatin and fenofibrate on serum lipoproteins and apolipoproteins in primary hypercholesterolaemia

Summary Sixteen patients with primary hypercholesterolaemia received double-blind either fenofibrate (n=8; 200 mg bid) or the HMG-CoA reductase inhibitor simvastatin (n=8; 20 mg qid or 40 mg qid if LDL-cholesterol did not fall below 3.6 mmol·l^–1 after 4 weeks of treatment).Simvastatin reduced total cholesterol from 9.7 to 7.0 mmol·l^–1 after 10 weeks (–28%), and fenofibrate reduced it from 9.2 to 7.7 mmol·l^–1 (–15%). The decrease was less during fenofibrate than during simvastatin treatment (time × drug:p=0.02).Serum LDL-cholesterol fell from 8.3 to 5.3 mmol·l^–1 (–36%) during simvastatin and from 7.2 to 6.0 mmol·l^–1 (–16%) during fenofibrate administration. Again, the effect of simvastatin was more pronounced than that of fenofibrate (time × drug:p=0.03).HDL-cholesterol increased significantly from 1.1 to 1.2 mmol·l^–1 (+13%) during fenofibrate administration and it did not change significantly during simvastatin.Serum triglycerides fell from 1.3 to 1.1 mmol·l^–1 (–16%) during simvastatin, and even more significantly from 2.2 to 1.1 mmol·l^–1 (–51%) during fenofibrate (time × drug:p=0.002).Apolipoprotein B fell on simvastatin from 1.9 to 1.4 g·l^–1 (–24%) and from 1.8 to 1.4 g·l^–1 (–22%) during fenofibrate.Both drugs were well tolerated and had no significant adverse effects.Simvastatin lowered total and LDL-cholesterol concentrations more than fenofibrate, while the latter had more effect on triglycerides, suggesting specific indications for the two drugs in the treatment of hyperlipoproteinaemias.     

Serum and saliva levels of a trimethoprim-sulfamethopyrazine combination in man

Summary The pharmacokinetics, hypotensive effect and tolerability of a new vasodilator, tolmesoxide (T), have been studied in 6 uncontrolled hypertensive patients receiving atenolol and a diuretic. After a 50 mg oral dose mean (± SD) peak plasma concentration of T was 1.13±0.29 µg/ml^–1 and occurred 0.79±0.40 h after the dose; mean peak plasma concentration of its sulphone metabolite (M) was 0.37±0.09 µg/ml^–1 at 1.92±1.32 h after the dose. Following peak plasma concentrations there was a monoexponential decline in T and M concentrations with half-lives of 2.78±0.77 h and 10.78±7.85 h respectively. There was a linear increase in plasma concentration of T and M during incremental dosing with 50–200 mg t. i. d. During in-patient administration of 600–900 mg T daily (n=6) there was no significant change in blood pressure, pulse rate or body weight. Out-patient administration of 900 mg T daily (n=4) was associated with a significant fall in mean systolic but not diastolic bp (lying –15/+1 mm Hg. standing –25/–8 mm Hg). A further fall was observed in 2 subjects receiving 1200 mg and 1500 mg daily. Supine pulse rate increased (mean ± SD) significantly from 55±5/min to 66±8/min following 900–1500 mg T in 4 out-patients. Severe nausea and other gastro-intestinal side-effects in all subjects receiving 600–900 mg daily eventually necessitated drug withdrawal. In its present from T is not recommended for the treatment of hypertension.     

Cimetidine-phenytoin interaction: Effect on serum phenytoin concentration and antipyrine test

Summary In a prospective study in nine patients the effects of phenytoin and of cimetidine (1000mg/day) + phenytoin on the antipyrine test and serum phenytoin concentrations were studied. Serum phenytoin increased from the steady state level of 5.7±1.3 mg/l to 9.1±1.4mg/l after three weeks on cimetidine (p<0.01), and fell to 5.8±1.2 mg/l within two weeks after withdrawal of cimetidine. The protein binding of phenytoin was not changed by cimetidine. After use of phenytoin for 2–4 months, antipyrine clearance increased from 0.67±0.06ml/min/kg to 1.61±0.22 ml/ min/kg, and antipyrine half-live fell from 10.9±1.3h to 4.5±0.6h as compared to the values before phenytoin treatment (p<0.01). After three weeks combined use of cimetidine and phenytoin, antipyrine clearance was decreased to 1.01±0.07 ml/min/kg and antipyrine half-life was prolonged to 6.1±0.5h, (p<0.01) compared to the values on phenytoin alone. The distribution volume of antipyrine was not affected by phenytoin nor by cimetidine + phenytoin. The half-life of cimetidine was 2.8±0.3h in the patients on longterm phenytoin treatment. There was a significant positive correlation (p<0.001) between the increase in serum phenytoin concentration and the prolongation of antipyrine half-life caused by cimetidine. Thus, cimetidine increases serum phenytoin concentration, very probably by inhibiting its metabolism. Care should be taken in the concomitant use of cimetidine and phenytoin, and the dose of phenytoin should be modified according to the clinical symptoms and serum phenytoin concentrations.Part of this work was presented at the Joint Meeting of the Scandinavian and German Pharmacological Societies, September 1980 [14]     

Induction of microsomal enzyme activity by flupenthixol in chronic schizophrenics

The effect of long-term treatment with flupenthixol on hepatic microsomal enzyme activity was studied in 12 chronic schizophrenic outpatients who had been receiving two weekly maintenance doses for at least 6 months. Antipyrine half-life was measured in the 12 patients while they continued to receive the drug. Flupenthixol was then discontinued for 6 weeks and antipyrine half-life was repeated in 7 of the 12 patients. In the 12 patients the plasma antipyrine elimination half-life was 4–24 h (mean 9.73±1.61 h) when receiving flupenthixol and there was a significant negative correlation between antipyrine half-life and the dose of flupenthixol (r=0.582, P<0.05). In the seven patients to whom antipyrine was given on two occasions, antipyrine half-life was 7.33±1.07 h and 12.04±1.87 h on and off flupenthixol treatment respectively. The clearance significantly decreased when flupenthixol was discontinued, but there was no change in the apparent volume of distribution.     

Thyroid hormone modulates membrane currents in guinea-pig ventricular myocytes

Summary Thyroid hormones have been previously shown to alter cardiac electrophysiological and mechanical properties in humans and in experimental animals. To investigate electrophysiological mechanisms responsible for some of these alterations, we recorded action potentials and membrane currents from isolated ventricular myocytes obtained from euthyroid, hypothyroid and hyperthyroid guinea-pigs. Hyperthyroidism was induced by injecting 150 g/kg triiodothyronine for 8–11 days, and hypothyroidism was induced by propylthiouracil treatment for 35–45 days. We found that the slow inward current, was increased by hyperthyroidism and decreased by hypothyroidism: in euthyroid, hyperthyroid and hypothyroid myocytes peak slow inward current was (mean ± SEM) : –1.08 ± 0.06 nA, –1.83 ±0.18^a nA and –0.64 ± 0.07^a nA, respectively (a,p < 0.005). In addition, the membrane potential at which peak slow inward current occurred was modified by the thyroid state and in euthyroid, hyperthyroid and hypothyroid myocytes it was (mean ± SEM): 4.8 ± 0.7 mV, –1.8 ± 1.6^a mV and 11.0 ± 1.4^a mV, respectively.The outward rectifying current, was also affected by the thyroid state, and in euthyroid, hyperthyroid and hypothyroid myocytes, the amplitude atV _M = + 60 mV was (mean ± SEM): 0.51 ± 0.09 nA, 1.15 ± 0.08^a nA and 0.49 ± 0.05 nA,respectively. a,p < 0.001 compared to euthyroid myocytes. Intraperitoneal administration of a single dose of triiodothyronine to guinea-pigs, 2 h prior to the electrophysiological experiment, increased the slow inward current amplitude, as was seen with chronic hyperthyroidism, but had no significant effect on the outward current and on the action potential. Finally, action potential and membrane currents were not altered by superfusing euthyroid myocytes with 10^–6 mol/l triiodothyronine for 30 min, or by introducing 10^–7 mol/l triiodothyronine into the cell through the recording pipette.From these findings we conclude that cardiac mechanical performance may be modulated by thyroid hormones through their effect on the slow inward current, while shortening of action potential duration is brought about, at least in part, by increasing the amplitude of the outward rectifying current. Send offprint requests to O. Binah at the above address     

Effects of papaverine on calcium efflux and contractility in superfused rat left atria

Summary The effects of papaverine upon force of contraction, maximal rate of contraction, maximal rate of relaxation and ⁴⁵Ca efflux were studied in isolated superfused rat left atria electrically driven at 1 Hz.Papaverine (3×10^–5 mol/l, increased developed tension (from 5.35±1.17 mN to 7.18±1.51 mN) by 1.8±0.41 mN (+33%, p<0.01) and maximal rate of contraction (+T) by 34.5±13% (p<0.05).In all experimental conditions tested, papaverine increased the rate of ⁴⁵Ca efflux. The amount by which papaverine increased ⁴⁵Ca efflux was 175±41 nmoles · g wet wt^–1 and 304±76 nmoles · g wet wt^–1, in the presence and in the absence of caffeine, respectively.The plot of changes in ⁴⁵Ca efflux versus changes in developed tension fitted to a straight line (r=+0.56, n=17, p<0.05), with a slope and intercept of 42 nmoles Ca · mN^–1 · g wet wt^–1 and –0.47 mN respectively, suggesting an association between the changes induced by papaverine in force development and increased ⁴⁵Ca efflux.     

Pharmacokinetics of midazolam in the aged

Summary The pharmacokinetics of midazolam, an imidazo-benzodiazepine derivative, have been studied in 13 subjects over the age of 60 years who received the drug intravenously (0.07 mg kg^–1) as an induction agent for endoscopy. Two to three days later, 6 of these subjects received 5 mg of midazolam intramuscularly, and another 6 of the subjects received 10 mg of the drug orally. The plasma concentration-time curves were again studied pharmacokinetically. After intravenous dosing, the mean (± SD) elimination half-life (2.14±1.24 h) showed a statistically significant trend to increase with age in the subjects older than 60 years. While the mean (± SD) clearance value (0.30±0.19 l kg^–1h^–1) tended to fall with age in the elderly subjects, this trend was not statistically significant. Apparent volume of distribution did not appear to be related to advancing age beyond 60 years, and this parameter (mean ± SD) did not differ to a statistically significant extent between the aged subjects (0.77±0.47 l kg^–1) and the young subjects studied previously (1.09±0.58 l kg^–1). Atropine premedication did not appear to alter the dispositional parameters of the intravenously administered drug. Intramuscularly administered midazolam was absorbed rapidly. Bioavailability appeared incomplete (F=0.59±0.15, mean ± SD), possibly due to saturable elimination of the drug at the higher plasma levels which were obtained after intravenous midazolam. Oral bioavailability, relative to intravenous, was 0.34±0.17, (mean ± SD), with an appreciable but variable lag time (0.74±0.40 h, mean ± SD). Orally, in the dose used, the drug was an inefficient hypnotic with four of the six subjects failing to attain the plasma drug level of 44–50 µg l^–1, which appeared to be the approximate threshold for sleep. It is impossible to know whether this failure represents an age related effect on drug absorption, or is a consequence of the upper alimentary tract abnormalities for which the endoscopies were done.     

Decreased renal clearance of digoxin in chronic congestive heart failure

Summary Renal digoxin clearance was compared in patients suffering from atrial fibrillation with well preserved cardiac function (n=9; salt intake ±170 mmol daily) and patients with chronic congestive heart failure (n=10; salt intake 50 mmol daily and maintenance treatment with diuretics). There was no difference between the groups concering digoxin dosage, creatinine clearance, diuresis or sodium excretion in the urine. Digoxin clearance in chronic heart failure proved to be significantly lower than in atrial fibrillation (48±21 vs 71±36 ml·min^–1, p<0.05), and Cdig/Ccreat was similarly reduced at 0.73±0.15 compared to 1.09±0.27 (p<0.005). Steady state serum digoxin concentration was significantly higher in patients with congestive heart failure (1.44±0.47 vs 0.87±0.33 µg·l^–1, p<0.01). Chronic congestive heart failure is a state with reduced digoxin clearance by the kidney, which could lead to digoxin intoxication not explicable by overdose, reduced renal function or the effect of interacting drugs.     

Combined Effects of Food Concentration and the Herbicide 2,4-Dichlorophenoxyacetic Acid on the Population Dynamics of Brachionus patulus (Rotifera)

Herbicides are important in crop protection and management. A number of them including 2,4-D (2,4-dichlorophenoxyacetic acid), however, may reach water bodies and eventually affect the non-target organisms such as rotifers. In the present work, we studied the influence of 6 concentrations viz. 0 (control), 100, 200, 300, 400 and 500 mg l^–1 of 2,4-D on the population growth of the rotifer Brachionus patulus under two algal (Chlorella) food levels (0.5×10⁶ and 1.5×10⁶ cells ml^{– 1}). Regardless of herbicide concentration, the population growth of B. patulus was dependent on the algal food levels, in that an increase in algal food level supported a better population growth. Similarly at any Chlorella density, the herbicide had a negative influence on the population growth of B. patulus. Herbicide level of 500 mg l^–1 inhibited population growth of B. patulus beyond 5 days. Rotifers grown under low food density and high herbicide concentration (300 mg l^–1 or above) were completely eliminated after day 15. The rate of population increase (r) (mean±standard error) in the controls varied from 0.46±0.002 and 0.55±0.004 under 0.5×10⁶ and 1.5×10⁶ cells ml^–1 of Chlorella, respectively. The r values became negative under both, low and high food levels, at or beyond 300 mg l^–1 of 2,4-D. The maximal population abundance (ind. ml^–1) in controls varied from 294±9 to 503±21 under low and high food levels of Chlorella, respectively. The role of algae in mitigating adverse effects of high herbicide concentrations to rotifers has been discussed.     

Effect of single- and multiple-dose carbamazepine on the pharmacokinetics of diphenylhydantoin

Summary A three-phase trial has been done in 11 volunteers. They were given 600 mg phenytoin (Dilantin capsules) in each phase after an overnight fast. In the first study, phenytoin was given alone. In the second phase 400 mg carbamazepine (CBZ) was given at the same time as the phenytoin, and in the third part, 200 mg CBZ t. d. s. was given for one week prior to the phenytoin. Blood samples were taken for 72 h in each phase. Plasma levels of phenytoin and CBZ were determined by HPLC, and plasma protein binding was determined by equilibrium dialysis.The unbound fraction of phenytoin was 0.082, 0.085, and 0.077 in the control, single-dose CBZ, multi-dose CBZ phases, respectively. Single and multiple doses of CBZ decreased the plasma level of phenytoin. The 72-h AUC of phenytoin was 276, 237, and 176 mg h·l^–1 in the 3 phases, respectively, and the 72-h AUC of unbound phenytoin was 22.8, 20.5, 13.0 mg h·l^–1. The AUC of phenytoin (unbound and total) after multiple doses of CBZ was significantly lower than in the other two phases. The apparent volume of distribution (V_z/f) was 89.9, 110.3, and 121.3 l in the 3 phases, respectively.Through pharmacokinetic analyses, the decreased AUC and increased V_z/f were attributed to decreased bioavailability of phenytoin when CBZ was co-administered.     

Effect of antipyrine coadministration on the kinetics of acetaminophen and lidocaine

Summary Pharmacokinetic interactions between antipyrine and acetaminophen were evaluated in 7 healthy volunteers. On 3 occasions subjects received:1, antipyrine 1.0 g intravenously (i.v.);2, acetaminophen 650 mg i.v.;3, antipyrine 1.0 g and acetaminophen 650 mg i.v. simultaneously.Between Trials 1 and 3, antipyrine elimination t_1/2 (17.2 vs 17.4 h), clearance (0.44 vs 0.43 ml·min^–1·kg^–1) and 24-h recovery of antipyrine and metabolites (313 vs 293 mg) did not differ significantly. Between Trials 2 and 3, acetaminophen V_z was reduced (1.14 vs 1.00 l·kg^–1), t_1/2 prolonged (2.7 vs 3.3 h), clearance reduced (4.8 vs 3.6 ml·min^–1·kg^–1), and fractional urinary recovery of acetaminophen glucuronide reduced.Eight additional subjects received 50 mg of lidocaine hydrochloride i.v. in the control state, and on a second occasion immediately after antipyrine 1.0 g given i.v.The two trials did not differ significantly in lidocaine V_z (2.6 vs 2.7 l·kg^–1), t_1/2 (2.0 vs 2.4 h) or clearance (15.0 vs 13.5 ml·min^–1·kg^–1).Although acetaminophen does not alter antipyrine kinetics, acute administration of antipyrine appears to impair acetaminophen clearance, possibly via inhibition of glucuronide formation. However, antipyrine has no significant effect on the kinetics of a single i.v. dose of lidocaine.     

In Vivo Assessment of Intestinal,Hepatic, and Pulmonary First Pass Metabolism of Propofol in the Rat

Purpose. The relative contribution of the intestinal mucosa, liver and lung to the in vivo disposition of propofol in the rat was investigated. Methods. Propofol (4.9–5.1 mg · kg^–l) was administered to groups of rats (n = 4) via the intra-arterial, intravenous, hepatic portal venous and oral routes. The AUC's of propofol were estimated and the fractions of the administered dose escaping first pass metabolism by the gut wall (f_G), liver (f_H) and lung (f_L) were calculated. In addition, transport experiments were carried out using Caco-2 cell monolayers to rule out the possibility that intestinal permeability is limiting the oral absorption of propofol. Results. Values for f_G, f_H and f_L were the following: 0.21 ± 0.07, 0.61 ± 0.13, and 0.82 ± 0.09, respectively. The apparent permeability coefficient of propofol across Caco-2 cell monolayers was 24.2 ± 0.3 × 10^–6 cm · sec^–1, which is similar to the apparent permeability coefficient obtained for propranolol (30.7 ± 1.7 × 10^–6 cm · sec^–1), a compound known to easily cross the intestinal epithelial membranes. The formation of propofol glucuronide, a major metabolite of propofol, could not be demonstrated during the flux experiments across the Caco-2 cell monolayers. Conclusions. The intestinal mucosa is the main site of first pass metabolism following oral administration of propofol in the rat. Intestinal metabolism could therefore also contribute to the systemic clearance of propofol.     

Altered thyroxin and retinoid metabolic response to 2,3,7,8-tetrachlorodibenzo-p-dioxin in aryl hydrocarbon receptor-null mice

To determine whether the disruption of thyroid hormone and retinoid homeostasis that occurs after exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can be mediated by the arylhydrocarbon receptor (AhR), pregnant AhR-heterozygous (AhR+/–) mice were administered a single oral dose of 10 g kg^–1 TCDD at gestation day 12.5. Serum and liver were collected on postnatal day 21 from vehicle-treated control or TCDD-treated AhR+/– and AhR-null (AhR–/–) mouse pups. Whereas TCDD exposure resulted in a marked reduction of total thyroxin (TT4) and free T4 (FT4) levels in the serum of AhR+/– mice, TCDD had no effects on AhR–/– mice. Gene expression of UDP-glucuronosyltransferase (UGT)1A6, cytochrome P450 (CYP)1A1, and CYP1A2 in the liver was induced markedly by TCDD in AhR+/– but not AhR–/– mice. Induction of CYP1A1 in response to TCDD was confirmed by immunohistochemical evidence in that CYP1A1 protein was conspicuously localized in the cytoplasm of hepatocytes in the centrilobular region. Levels of retinyl palmitate were greatly reduced in the liver of TCDD-exposed AhR+/– mice, but not in vehicle-treated AhR+/– mice. No effects of TCDD on retinoid levels in the liver were found in AhR–/– mice. We conclude that disruption of thyroid hormone and retinoid homeostasis is mediated entirely via AhR. Induction of UGT1A6 is thought to be responsible at least partly for reduced serum thyroid hormone levels in TCDD-exposed mice.     

Pharmacokinetic interaction of chloroquine and methylene blue combination against malaria

Objective The combination of chloroquine and methylene blue is potentially effective for the treatment of chloroquine-resistant malaria caused by Plasmodium falciparum. The aim of this study was to investigate whether methylene blue influences the pharmacokinetics of chloroquine.Methods In a randomized, placebo-controlled, parallel group design, a 3-day course of therapeutic oral doses of chloroquine (total 2.5 g in male, 1.875 g in female participants) with oral co-administration of placebo or 130 mg methylene blue twice daily for 3 days was administered to 24 healthy individuals. Chloroquine, desethylchloroquine, and methylene blue concentrations were determined by means of HPLC/UV or LC/MS/MS assays in whole blood, plasma, and urine for 28 days after the last dose.Results During methylene blue exposure, the area under the chloroquine whole blood concentration–time curve normalized to body weight (AUC_{0-24 h}/BW) yielded a trend of reduction (249±98.2 h g l^–1 kg^–1 versus 315±65.0 h g l^–1 kg^–1, P=0.06). The AUC_{0-24 h}/BW of desethylchloroquine was reduced by 35% (104±40.3 h g l^–1 kg^–1 versus 159±66.6 h g l^–1 kg^–1, P=0.03), whereas the metabolic ratio between chloroquine and desethylchloroquine remained unchanged (2.25±0.49 versus 1.95±0.42, P=0.17). The renal clearance of chloroquine and the ratio between chloroquine in whole blood and plasma remained unchanged (P>0.1).Conclusion Oral co-administration of methylene blue appears to result in a small reduction of chloroquine exposure which is not expected to be clinically relevant and thus represents no concern for further development as an anti-malarial combination.     

Population Pharmacokinetic Modeling of Steady State Carbamazepine Clearance in Children, Adolescents, and Adults

Carbamazepine (CBZ) clearance decreases from childhood to adulthood and the factors determining this change could include age, size, autoinduction, or maturational changes. This study aims to describe the population pharmacokinetics of CBZ in children and young adults and test the hypothesis that CBZ clearance correlates with weight, surface area, and age. CBZ therapeutic drug monitoring data (sparse data) were collected from child and adult epileptics, and rich data were obtained from a bioequivalence study of CBZ in young adults. Population pharmacokinetic analysis was performed using NONMEM V. Forward stepwise, multiple regression was performed on the covariates. Bootstrap validation was performed. A total of 946 observations from 91 subjects, ages 0.7–37 years, were collected and analyzed. A one-compartment, first-order absorption and elimination model, with exponential interindividual error and additive residual error models was developed. The population model was: Clearance (Lhr ^–1)=((2.24 · Surface area (m ²))+(0.047 · Dose (mg · kg ^–1)); Volume of distribution (L)=0.37 · weight (kg); Absorption rate constant=0.013 (hr ^–1). CBZ clearance increased with surface area and dose.