Pharmacokinetics and pharmacodynamics of ()-sotalol in healthy male volunteers

1 We investigated the pharmacokinetics and pharmacodynamics of (±)-sotalol administered orally to healthy male volunteers in single doses of 40, 80 and 160 mg and in multiple doses of 80 mg twice daily for 7 consecutive days.
2 In the single dose studies, the half-life of (-)-sotalol (7.2-8.5 h) was significantly ( P < 0.01) shorter than that of (+)-sotalol (9.1-11.4 h) while the renal clearance of (-)-sotalol (110.6-126.4 ml min^-1) was significantly ( P < 0.01) faster than that of (+)-sotalol (102.2-110.1 ml min^-1). In the multiple dose studies, similar differences in the pharmacokinetics of (+)- and (-)-sotalol were observed. In addition, the pharmacokinetics of both (+)- and (-)-sotalol on day 4 were shown to be essentially the same as those on day 7.
3 In pharmacodynamic examinations, (±)-sotalol prolonged QTc intervals on electrocardiograms dose-dependently after single doses of 80 and 160 mg (3.81 ± 2.96%, 13.23 ± 5.66%). The correlation between the plasma concentration of (±)-sotalol and prolongation of QTc intervals was nearly linear, and showed no hysteresis.
4 In conclusion, we demonstrated that QTc interval was prolonged with a linear correlation to the plasma concentration of (±)-sotalol. In addition, our study suggested that differences in the pharmacokinetics of (+)- and (-)-sotalol may be attributable to faster urinary excretion of (-)-sotalol.     

The airway effects of stopping regular oral theophylline in patients with asthma

Aims We investigated whether the deterioration in asthma control reported following cessation of theophylline was due to tolerance to theophylline.
Methods Eighteen subjects with mild stable asthma were given oral theophylline 10  mg  kg⁻¹ day⁻¹ or placebo for 2 weeks in a double-blind crossover study. FEV₁ and PD₂₀ histamine were measured before and 8  h after the first dose of treatment and 8, 32 and 56  h after the final dose. PD₂₀ AMP was measured before treatment and 9  h after the final dose.
Results Six patients did not tolerate theophylline. In the other 12 subjects there were no differences between treatments in daily PEF, symptom scores, rescue bronchodilator use, PD₂₀ histamine or FEV₁ up to 8  h post treatment. Following withdrawal of theophylline there were significantly lower values for mean FEV₁ (mean difference 0.15  l, 95% CI 0.03, 026) and PD₂₀ AMP compared to placebo but no difference in other end points.
Conclusions The small rebound deterioration in lung function following regular treatment with therapeutic doses of oral theophylline is consistent with the development of tolerance.     

Tolerance to the repolarization effects of 'oorac'ox-sotalol during long-term treatment

Aims To establish whether tolerance to the QT effect could ensue during maintenance treatment with rac -sotalol.
Methods The effect of rac -sotalol on QT interval duration was studied in 10 patients after single oral administration (160  mg) and after 6-day multiple oral dosing (80  mg two or three times daily). In order to separate the pure Class III effect from the bradycardia-related QT prolongation, heart rate/QT relationship was preliminarly assessed in each patient after the administration of a pure &bgr;-adrenoceptor blocker (propranolol, 80  mg orally). Repolarization changes were quantified as percent difference between the measured QT and the expected QT on the basis of the individual heart rate/QT relationship.
Results In all patients QT interval prolongation was linearly correlated with rac -sotalol log plasma concentration. The maximal QT prolongation and peak plasma concentration were not significantly different following acute and chronic administrations (QT effect: +18.1±6.3% vs +14.2±3.3%; peak concentration: 1.64±0.49  mg  l⁻¹ vs 1.83±0.66  mg  l⁻¹ ). Line slopes were also unchanged following chronic treatment (21.8±8.9 vs 21.1±9.2). In four cases a significant rightward shift of the line occurred during repeated administrations, consistent with the appearance of pharmacodynamic tolerance. The inconstancy of this change in responsiveness may either be ascribed to a genetically determined individual susceptibility or to a variable interplay between Class III effect, gradual QT prolongation due to long-term &bgr;-adrenoceptor blockade and tolerance development.
Conclusions During maintenance treatment with rac -solatol, partial loss of repolarization effects occurred in some patients suggesting pharmacological tolerance.     

Stimulatory as well as inhibitory effects of ethinyloestradiol on the metabolic clearances of propranolol in young women

1   The metabolism of a single 80  mg oral dose of propranolol was determined in nine young women before and after administration of ethinyloestradiol alone (EE₂) or in combination with norethindrone (OC).
2   Whereas the total clearance of propranolol (2713±404  ml min⁻¹ (mean±s.e.mean)) was not significantly altered by either EE₂ (3365±347  ml min⁻¹) or the combined OC (2905±345  ml min⁻¹), significant changes in all three primary metabolic pathways were observed.
3   The clearance through side-chain oxidation decreased from 345±55  ml min⁻¹ to 262±33  ml min⁻¹ after EE₂ ( P <0.05). A similar reduction of cytochrome P450 metabolism by EE₂ has been observed for other drugs.
4   The clearance through glucuronidation increased from 364±61  ml min⁻¹ to 625±117  ml min⁻¹ after EE₂ ( P <0.01). Similar stimulation of glucuronic acid conjugation by EE₂ has also been observed for other drugs.
5   The clearance through ring oxidation increased from 697±109  ml min⁻¹ to 1280±162  ml min⁻¹ after EE₂ ( P <0.01). This observation appears to be a novel finding with EE₂ and cytochrome P450 metabolism.
6   The treatment with OC produced changes in propranolol's metabolic clearances which were qualitatively similar to those generated by EE₂.     

Pharmacokinetics of the individual enantiomers of vigabatrin in neonates with uncontrolled seizures

The antiepileptic drug vigabatrin (VGB) is a selective irreversible inhibitor of GABA-transaminase. It is administered as a racemic R(−), S(+) mixture, but the pharmacological activity of vigabatrin resides in the S(+) enantiomer and the R(−) enantiomer is inactive. The pharmacokinetic parameters of the two enantiomers have been studied after administration of a single oral 125  mg dose of the racemate to six neonates. The mean values of C _max and AUC of the S(+) enantiomer were significantly lower ( C _max : 14.0±4.3  mg l⁻¹; AUC: 143±44  mg l⁻¹  h) than those of the R(−) enantiomer ( C _max: 34.1±9.5  mg l⁻¹; AUC: 231±88  mg l⁻¹  h), whereas no significant difference in the time to reach C _max (S(+): 2.1±1.1  h; R(−): 2.2±1  h) was observed between the two enantiomers. During chronic administration (125  mg twice daily over 4 days), there was no evidence of accumulation of either enantiomer.     

Effect of intravenous magnesium sulphate on airway calibre and airway reactivity to histamine in asthmatic subjects

In a randomized, double-blind, placebo controlled cross-over study we have investigated the effect of intravenous magnesium on airway calibre and airway reactivity to histamine in 20 subjects with mild to moderate asthma. After baseline measurements of forced expiratory volume in one second (FEV₁), subjects received 100 ml normal saline with or without 2 g of magnesium sulphate by infusion over 20 min. Measurements of FEV₁ were repeated at 5 min intervals throughout the infusion, and the provocative dose of histamine required to drop the FEV₁ by 20% from baseline ( PD ₂₀FEV₁) was determined at 20 min. The area under the curve (AUC) in litre minutes for change from baseline in FEV₁ between 0 and 20 min was significantly higher on the magnesium study day (mean difference in AUC (95% CI) 1.71 (0.02-3.4), P = 0.049). The increase in FEV₁ from baseline with magnesium relative to saline was maximal at 20 min (mean difference (95% CI) 0.13 (0.02-0.23) 1, P = 0.01). Log P D ₂₀FEV₁ to histamine was not significantly different after magnesium and saline (mean difference in log P D ₂₀FEV₁ (95% CI) 0.04 (-0.19 to 0.27), P = 0.7). We conclude that intravenous magnesium is a weak bronchodilator but does not alter airway reactivity at this dose in stable asthmatic subjects.     

Nitric oxide: an important role in the maintenance of systemic and pulmonary vascular tone in man

Aims The aim of this study was to examine whether nitric oxide (NO) has an important role in maintaining basal vascular tone in normal man by examining the effects of nitric oxide inhibition using N ^G-monomethyl-l-arginine (l-NMMA) on systemic and pulmonary haemodynamics.
Methods Ten normal male volunteers 26±1.6 years were studied on two separate occasions in a double-blind, placebo controlled crossover study. They were randomised to receive either a continuous infusion of l-NMMA (4  mg  kg⁻¹  h⁻¹ ) with a front loaded bolus (4  mg  kg⁻¹ ) or volume matched placebo. Pulsed wave Doppler echocardiography was used to measure cardiac output (CO), mean pulmonary artery pressure (MPAP) and hence systemic vascular resistance (SVR) and total pulmonary vascular resistance (TPR). Measurements were made prior to infusion ( t ₀ ) and after 4, 8, and 12  min ( t ₁, t ₂ and t ₃ ).
Results Infusion of l-NMMA significantly increased mean arterial blood pressure (MAP), SVR and TPR and significantly reduced heart rate (HR), stroke volume (SV) and CO compared to placebo. These effects were observed at t ₁ and persisted during the entire infusion period.
Conclusions These results are consistent with a role for basal nitric oxide generation in the maintenance of basal systemic and pulmonary vascular tone in normal man.     

Enantioselective pharmacokinetics of mefloquine during long-term intake of the prophylactic dose

Aims To investigate the kinetics of the (+)RS- and (−)SR-enantiomers and the carboxylic acid metabolite (MMQ) of the antimalarial drug mefloquine (MQ) in healthy volunteers.
Methods Ten subjects of which three were poor metabolizers of debrisoquine received racemic MQ 250  mg once weekly for 16 weeks. The kinetics were followed in plasma and urine and evaluated by individual kinetic modelling as well as by a nonparametric population kinetic method.
Results A two-compartment model adequately described the disposition of (+)RS-MQ. CL/ F was 6.5±1.8 l  h⁻¹, V _ss/ F 815±165  l, and k 0.0081± 0.0023  h⁻¹. The kinetics of (−)SR-MQ were time- and/or concentration dependent with a lower oral clearance (0.92±0.25 vs 2.14±0.63 l h⁻¹, 95% CI for the difference 0.86–1.60 l h⁻¹ ) and a longer half-life (345 vs 185  h, 95% CI for the difference 47–291  h) after the last dose compared with the first dose. Clearance of (+)RS-MQ and (−)SR-MQ was significantly correlated within subjects ( r =0.69, P <0.05). Urinary recovery of unchanged substance was 8.7% for (+)RS-MQ and 12.3% for (−)SR-MQ. The elimination of MMQ was disposition rate-limited and not determined by its rate of formation. Poor metabolizers of debrisoquine did not differ from extensive metabolizers in the kinetics of any compound.
Conclusions The MQ enantiomers differ extensively in their disposition both with regard to parameter values and the kinetic stability over time during repeated dosing with racemic MQ. Kinetic modelling of racemic MQ is therefore inadequate.     

No effect of short-term omeprazole intake on acenocoumarol pharmacokinetics and pharmacodynamics

Aims To investigate the effect of omeprazole on the pharmacokinetics of R- and S-acenocoumarol and on their combined anticoagulant activity.
Methods Eight healthy male subjects completed a double-blind, randomized, placebo-controlled, two-way cross-over study. Subjects were given either omeprazole 40  mg or placebo once daily for 3 days. On day 2 of each study period, a single 10  mg oral dose of racemic acenocoumarol was administered and venous blood samples were collected for pharmacokinetic and pharmacodynamic assessments. A wash-out period of 2 weeks separated the two study periods.
Results The pharmacokinetics of R- and S-acenocoumarol (AUC 3016±221 and 233±14  ng  ml⁻¹ h, respectively) did not change after omeprazole (AUC 2929±256 and 220±18  ng  ml⁻¹ h, respectively). Anticoagulant activity (INR_max 1.7±0.1) was unaffected by co-administration of omeprazole (INR_max 1.7±0.1).
Conclusions The short-term intake of omeprazole does not affect acenocoumarol pharmacokinetics or pharmacodynamics. These data differ from the results of previous studies on the effect of omeprazole on warfarin, suggesting a different in vivo interaction profile of omeprazole on acenocoumarol than on warfarin. Drug interaction studies with oral anticoagulants should not be restricted to the use of warfarin.     

Absorption kinetics of oral sotalol combined with cisapride and sublingual sotalol in healthy subjects

Aims To study the absorption kinetics of sotalol following administration of different formulations. A formulation which results in fast absorption might be useful in the episodic treatment of paroxysmal supraventricular tachycardia (SVT), atrial fibrillation (Afib) or atrial flutter (Afl).
Methods In an open randomized crossover study seven healthy male volunteers were given an intravenous infusion of 20  mg sotalol, for assessing the absolute bioavailability, an oral solution containing 80  mg sotalol, an oral solution containing both 80  mg sotalol and 20  mg cisapride and an 80  mg sotalol tablet, which was taken sublingually.
Results The addition of cisapride decreased the time at which maximum serum concentrations were reached ( t _max ) from 2.79 (1.85–4.34) h to 1.16 (0.68–2.30) h ( P =0.009) [95% CI: -2.59, −0.55] and increased the absorption rate constant ( k _a ) from 0.49 (0.31–0.69) h⁻¹ to 1.26 (0.52–5.61) h⁻¹ ( P =0.017). The absolute bioavailability of sotalol was reduced by cisapride from 1.00±0.15 to 0.70±0.26 ( P =0.006), while maximum serum concentrations of both oral solutions were not significantly different. Compared with the sublingually administered tablet with a median t _max of 2.12 (0.89–3.28) h, the sotalol/cisapride oral solution gave a smaller t _max (p=0.009) [95% CI: −1.64, −0.36]. The k _a of the sotalol/cisapride solution was significanty ( P =0.010) larger than the k _a of 0.56 (0.33–0.75) h⁻¹ found after sublingual administration of the tablet.
Conclusions The sotalol/cisapride oral solution might be suitable for the episodic treatment of SVT, Afib or Afl.     

Pharmacodynamics of oxypurinol after administration of allopurinol to healthy subjects

1   Eight healthy subjects received 50, 100, 300, 600 and 900  mg allopurinol daily for 1 week each, in random order with 1 week separating each treatment period. The pre-dose plasma concentration of oxypurinol, the extent of inhibition of xanthine oxidase, plasma urate concentration and urine urate excretion rate were assessed on the last 2 days of each treatment week.
2   The ratio of 1-methyluric acid (1MU) over 1-methylxanthine (1MX) in the urine, following a dose of 50  mg 1MX infused intravenously over 20  min, was used to measure the inhibition of xanthine oxidase.
3   The steady-state plasma concentration of oxypurinol increased linearly with increasing dose of allopurinol between 50  mg to 600  mg day⁻¹, with a weak indication of saturation at the higher 900  mg day⁻¹ dose rate.
4   The relationships between plasma oxypurinol concentration and xanthine oxidase inhibition (1MU/1MX ratio), plasma urate concentration and urine urate excretion rate were fitted to an inhibition sigmoid E_max model and the C ₅₀ values for oxypurinol were 26.38±4.87, (mean±s.d.) 36.58±8.36 and 24.61±9.08  μm, respectively.
5   1MU/1MX ratio appeared to be a reliable index of xanthine oxidase activity in vivo as the C ₅₀ for oxypurinol observed for 1MU/1MX ratio, plasma urate concentration and urine urate excretion rate were similar.
6   The concentration of oxypurinol required for inhibition of xanthine oxidase, as indicated by C ₅₀, was lower than those often observed in clinical practice.     

A novel partial 5HT3 agonist DDP733 after a standard refluxogenic meal reduces reflux events: a randomized, double-blind, placebo-controlled pharmacodynamic study

Background  DDP733, a selective partial 5HT₃ receptor agonist, increases lower oesophageal sphincter pressure in experimental animal models. However, its effect on gastro-oesophageal reflux or lower oesophageal sphincter pressure in humans remains unknown.
Aim  To evaluate the effect of DDP733 on reflux episodes in healthy volunteers receiving a refluxogenic meal.
Methods  A randomized, double-blind, placebo-controlled cross-over study evaluated the pharmacodynamic effects of DDP733 (0.5, 0.8 and 1.4 mg). Healthy subjects underwent oesophageal manometry and intra-oesophageal multichannel intraluminal impedance and pH after a refluxogenic meal.
Results  DDP733 0.5 mg significantly ( P  = 0.013) reduced the rate of reflux episodes after a refluxogenic meal from 10 (±2.2) on placebo to 6 (±1.2) on drug over a 2-h period. DDP733 0.8 and 1.4 mg had no significant effect on reducing the number of reflux episodes. Significant differences in resting lower oesophageal sphincter pressure and the proportion of time pH was <4 (placebo minus drug) after a refluxogenic meal were not observed. No serious adverse events were reported.
Conclusion  In healthy subjects, the partial 5HT₃ agonist DDP733 at a dose of 0.5 mg significantly reduces the rate of reflux events, but did not result in a significant change in lower oesophageal sphincter pressure at 1 h postdosing.     

Diazepam–omeprazole inhibition interaction: an in vitro investigation using human liver microsomes

1 The metabolism of diazepam to its primary metabolites 3-hydroxydiazepam (3HDZ) and nordiazepam (NDZ) was evaluated in human liver microsomes. The 3HDZ pathway was the major route of metabolism representing 90% of total metabolism with a V _max /K _m ratio of 0.50–7.26  μl  min⁻¹  mg ⁻¹ protein.
2 Inhibition of the two metabolic pathways of diazepam by omeprazole was investigated. The NDZ pathway was not affected by omeprazole whilst a K _i of 201±89  μm was obtained for the 3HDZ pathway ( K _m /K _i ratio of 3.0±0.9).
3 Inhibitory effects of omeprazole sulphone on the 3HDZ and NDZ pathways were also investigated. Omeprazole sulphone inhibited both pathways with similar K_is of 121±45 and 188±73  μm respectively ( K _m /K _i ratios of 5.2±2.3 and 3.3±1.5 respectively).
4 These in vitro data provide direct evidence for cytochrome P450 inhibition as the mechanism for the well documented diazepam-omeprazole clinical interaction and indicate that omeprazole sulphone, as well as the parent drug, contribute to the inhibition effect.     

Erythropoietin production in healthy volunteers subjected to controlled haemorrhage: evidence against a major role for adenosine

1 This study was carried out to assess the role of adenosine in the regulation of human erythropoietin (EPO) production. To this end we investigated in healthy volunteers whether the nonspecific adenosine antagonist theophylline increases and the adenosine uptake inhibitor dipyridamole decreases EPO production in response to an haemorrhage of 750  ml.
2 Healthy male nonsmokers received i.v. in a parallel, randomized, single-blind trial theophylline (loading dose 5  mg  kg⁻¹ over 20  min, followed by 0.5  mg  kg⁻¹ min⁻¹), dipyridamole (0.21  mg  kg⁻¹ h⁻¹) or placebo (0.9% NaCl) for 6  h following the phlebotomy. EPO concentrations were followed up to 72  h after phlebotomy.
3 Following blood loss EPO concentrations increased during all treatments. The AUC_EPO (0,72  h) were not statistically significantly different (theophylline: 398±30, dipyridamole: 301±15, placebo: 332±57 [mu  ml⁻¹ h]). Creatinine clearance and urinary cAMP excretion were unaltered by any treatment. Urinary excretion of adenosine was significantly increased during infusion of dipyridamole. Plasma renin activitiy was significantly increased during theophylline infusion.
4 In our model of controlled, physiological stimulation of EPO production by haemorrhage, adenosine appears unlikely to play a major role as a mediator of renal EPO production.     

Cyclosporin pharmacokinetics following administration of capsules and Neoral in paediatric patients with lupus nephritis

Aims Neoral is a new microemulsion form of cyclosporin. Pharmacokinetic reports in children are scarce. Therefore, we performed a pharmacokinetic study between Cyclosporin A (CsA) capsules and Neoral in paediatric patients with lupus nephritis.
Methods A single 5  mg  kg⁻¹ dose orally of either CsA capsules or Neoral was given to 10 paediatric patients (serum creatinine<1.5  mg dl⁻¹ ). CsA whole blood levels were measured for 24  h post-dose by h.p.l.c.
Results Neoral had a higher C _max and AUC( C _max: 943±176  ng  ml⁻¹; AUC: 4612±785  ng  ml⁻¹  h) than those of the CsA capsules ( C _max: 697±187  ng  ml⁻¹; AUC: 3483±873  ng  ml⁻¹  h; P <0.05). There was no difference in t _max and t _1/2,z between the two groups.
Conclusions CsA Neoral had improved absorption and bioavailability, which is similar to what is reported in adults. However, interpatient variability still existed. Careful drug monitoring and dose adjustment should be performed during treatment to avoid nephrotoxicity, especially in lupus nephritis.     

The effects of ketoconazole on ziprasidone pharmacokinetics —a placebo‐controlled crossover study in healthy volunteers

Aims   To assess the effects of multiple oral doses of ketoconazole on the single‐dose pharmacokinetics of oral ziprasidone HCl.
Methods   This was a 14‐day, open‐label, randomized, crossover study in 14 healthy subjects aged 18–31 years. Group 1 received oral ketoconazole 400 mg once daily for 6 days, followed by a 2 day wash‐out period and 6 days of placebo administration. Group 2 received placebo followed by ketoconazole. Single oral doses of ziprasidone HCl 40 mg were administered on days 5 and 13 in both groups. Ziprasidone pharmacokinetic parameters were compared between placebo and ketoconazole administration periods.
Results   Co‐administration of ziprasidone with ketoconazole was associated with a modest increase in ziprasidone exposure; mean ziprasidone AUC(0,∞) increased by 33%, from 899 ng ml^{− 1} h with placebo to 1199 ng ml^{− 1} h with ketoconazole. Mean C _max increased by 34%, from 89 ng ml^{− 1} to 119 ng ml^{− 1}, respectively. The treatment effect on both of these parameters was statistically significant ( P < 0.02). Most adverse events were of mild intensity. There were no serious adverse events, laboratory abnormalities, abnormal ECGs, or clinically significant alterations in vital signs throughout the study.
Conclusions   The concurrent administration of ketoconazole and ziprasidone led to modest, statistically significant increases in ziprasidone exposure, although the changes seen were not considered clinically relevant. This suggests that other inhibitors of CYP3A4 are unlikely to significantly affect the pharmacokinetics of ziprasidone.     

The pharmacokinetics of ziprasidone in healthy volunteers treated with cimetidine or antacid

Aims  To evaluate the effects of cimetidine and Maalox^® (aluminium hydroxide 1.35 g and magnesium hydroxide 1.2 g) on the pharmacokinetics of ziprasidone.
Methods   Eleven healthy young subjects aged 18–45 years were given single oral doses of ziprasidone 40 mg on three occasions at least 7 days apart. On one occasion ziprasidone was administered alone, on another occasion ziprasidone was co‐administered with oral cimetidine 800 mg and on a third occasion ziprasidone was co‐administered with oral Maalox^®.
Results   The administration of cimetidine increased the ziprasidone AUC(0,∞) by 6% but there were no statistically significant differences in C _max, t _max or λ_z between the ziprasidone+cimetidine group and the ziprasidone group. The administration of Maalox^® did not produce any statistically significant differences in AUC(0,∞), C _max, t _max or λ_z between the ziprasidone+Maalox^® group and the ziprasidone group.
Conclusions   The pharmacokinetics of ziprasidone are not affected by concurrent administration of cimetidine or Maalox^®. This suggests that other nonspecific inhibitors of cytochrome P450 and antacids are unlikely to alter the pharmacokinetics of ziprasidone.     

(−)-Timolol is a more potent antagonist of the positive inotropic effects of (−)-adrenaline than of those of (−)-noradrenaline in human atrium

1 The affinity of (−)-timolol for β₁- and β₂-adrenoceptors was determined on isolated atrial preparations from patients undergoing open heart surgery. The times for onset and offset of antagonism of the positive inotropic effects of (−)-adrenaline and (−)-noradrenaline by (−)-timolol were measured.
2 The antagonism of the positive inotropic effects of (−)-adrenaline and (−)-noradrenaline by (−)-timolol (0.1–100 nm) was simple competitive in human atrium tissue. The slope of Schild-plots was not significantly different from 1.0 [0.93±0.09 for (−)-adrenaline, 0.97±0.09 for (−)-noradrenaline].
3 The inotropic effects of (−)-adrenaline were antagonized significantly more by each concentration of (−)-timolol than those of (−)-noradrenaline. K _B-values (-log m) were 10.10±0.09 against (−)-adrenaline and 9.43±0.07 against (−)-noradrenaline ( P <0.001).
4 Blocking kinetics of (−)-timolol for the β-adrenoceptor were relatively slow. Half-times for the onset of blockade by 10 times K _B of (−)-timolol were approximately 30  min for both (−)-adrenaline and (−)-noradrenaline; offset times were similar.
5 It is concluded that (−)-timolol has a higher affinity for the β₂-adrenoceptor than for the β₁-adrenoceptor in human atrium. This property may be beneficial clinically in protecting against the β₂-adrenoceptor hypersensitivity induced by cardiac β₁-adrenoceptor blockade, but also explain why severe asthma can occur after administration of very low intra-ocular doses of the drug.     

The induction effect of rifampicin on activity of mephenytoin 4''-hydroxylase related to M1 mutation of CYP2C19 and gene dose

Aims To determine the induction effect of rifampicin on the activity of 4'-hydroxylase in poor metabolizers (PMs) with m₁ mutation of S-mephenytoin 4'-hydroxylation and the relationship of the effect with gene dose.
Methods Seven extensive metabolizers (EMs) of S-mephenytoin 4'-hydroxylation and five PMs with m₁ mutation were chosen to take rifampicin 300  mg day⁻¹ orally for 22 days. Prior to and after rifampicin treatment, each subject was given racemic mephenytoin 100  mg. The 4'-hydroxymephenytoin (4'-OH-MP) excreted in the 0–24  h urine and mephenytoin S/R ratio in the 0–8  h urine were determined by h.p.l.c. and GC, respectively.
Results In all EMs, the excretion of 4'-OH-MP in the 0–24  h urine was increased by 146.4±17.9%, 0–8  h urinary mephenytoin S/R ratio was decreased by 77.3±8.8%, the percentage increase in the 0–24  h excretion of 4'-OH-MP in those CYP2C19 homozygous (wt/wt) was greater than that in those heterozygous (wt/m₁ and wt/m₂ ) (203.9±42.5% vs 69.6±4.1%). 0–8  h urinary mephenytoin S/R ratio of those PMs with m₁ mutation was decreased by 9.6%, the amount of 4'-OH-MP excreted in the 0–24  h urine was increased by 80.1±48.0%.
Conclusions The activity of 4'-hydroxylase of PMs with m₁ mutation of S-mephenytoin 4'-hydroxylation can be induced by rifampicin and the inducing effect of rifampicin on 4'-hydroxylase is gene dependent.     

Single dose pharmacokinetics of oral artemether in healthy Malaysian volunteers

Aims To determine the pharmacokinetics of artemether (ARM) and its principal active metabolite, dihydroartemisinin (DHA) in healthy volunteers.
Methods Six healthy male Malaysian subjects were given a single oral dose of 200  mg artemether. Blood samples were collected to 72  h. Plasma concentrations of the two compounds were measured simultaneously by reversed-phase h.p.l.c. with electrochemical detection in the reductive mode.
Results Mean (± s.d.) maximum concentrations of ARM, 310±153  μg  l⁻¹, were reached 1.88±0.21  h after drug intake. The mean elimination half-life was 2.00±0.59  h, and the mean AUC 671±271  μg  l⁻¹ h. The mean C _max of DHA, 273±64  μg  l⁻¹, was observed at 1.92±0.13  h. The mean AUC of DHA was 753±233  μg  h  l⁻¹. ARM and DHA were stable at ≤−20°  C for at least 4 months in plasma samples.
Conclusions The relatively short half-life of ARM may be one of the factors responsible for the poor radical cure rate of falciparum malaria with regimens employing daily dosing. In view of the rapid loss of DHA in plasma samples held at room temperature (26°  C) it is recommended to store them at a temperature of ≤−20°  C as early as possible after sample collection.