Pharmacokinetics of phenytoin in children.

1 Apparent Vmax and Km for phenytoin were estimated in 40 children (aged 8--33 months) and 21 adults (aged 18--66 years). 2 The derived values of Vmax and Km were used to predict the plasma and salivary concentrations of phenytoin following a change in dose. There was a highly significant correlation between observed and predicted steady-state concentration in both children and adults (P less than 0.001). 3 The apparent Km was similar in children (7.5 +/- 1.2 mg/l) and adults (9.4 +/- 2.3 mg/l). 4 Vmax differed significantly (P less than 0.001) between children (20.4 +/- 2.1 mg kg-1 day-1) and adults (8.7 +/- 0.7 mg kg-1 day-1). 5 After correction for differences in the ratio of liver weight to body weight in children and adults, Vmax was similar in the two groups.     

Protein binding and CSF penetration of phenytoin following acute oral dosing in man.

Prophylactic phenytoin (DPH) has been evaluated in 20 patients undergoing diagnostic myelography. DPH (0.75 g) was ingested at 20.00 h the night before and 0.5 g at 08.00 h on the morning of the procedure. Total DPH concentrations at myelography (mean +/- s.d.: 12.7 +/- 4.3 mg l-1; range 6.3-21.5 mg l-1) correlated with CSF values (1.3 +/- 0.46 mg l-1; range 0.7-2.2 mg l-1; r = 0.83, P less than 0.001). DPH protein binding at that time varied two-fold (9.2-18.5%) and free drug levels (1.7 +/- 0.6 mg l-1) correlated with CSF (r = 0.83, P less than 0.001) and total (r = 0.89, P less than 0.001) plasma DPH concentrations. There were significant negative correlations between patient weight (n = 17) and total (r = 0.57, P less than 0.05) and CSF (r = -0.55, P less than 0.05) DPH concentrations at myelography. Total plasma DPH levels 8 h (14.5 +/- 3.9 mg l-1; range 7.3-20.6 mg l-1) and 24 h (12.3 +/- 3.8 mg l-1; range 5.0-19.8 mg l-1) after myelography were largely within the 'therapeutic range' of 10-20 mg l-1 for the drug. No patient suffered a seizure although, in two, spike discharges were seen on a post-myelography electroencephalogram. A simple regime involving two doses of DPH would provide acceptable plasma CSF concentrations as a basis for controlled studies in seizure prophylaxis following neuroradiological investigations involving intrathecal contrast.     

Oral phenytoin pharmacokinetics during omeprazole therapy.

1. In a double-blind crossover study 10 healthy males received either placebo or omeprazole (40 mg day-1) for 9 days, a single dose of phenytoin (300 mg) being taken on the seventh day. 2. Omeprazole significantly increased the area under the curve (0 to 72 h) of phenytoin (mean +/- s.e. mean) from 121.6 +/- 14.0 to 151.4 +/- 13.6 micrograms ml-1 h) (P less than 0.01). 3. The peak concentration, and apparent elimination half-life of phenytoin also tended to be increased though not significantly. 4. The omeprazole-phenytoin interaction observed may be clinically important because of the low therapeutic index associated with phenytoin.     

Serum level monitoring of a new slow release theophylline formulation in patients with chronic lung disease.

1 Serum theophylline levels were performed in 26 patients with chronic lung disease receiving rapid release theophylline (125 mg 6 hourly) and 28 patients receiving slow release theophylline (250 mg 12 hourly) under steady state conditions. 2 For rapid release theophylline the mean +/- s.d. serum theophylline levels at 0 and 2 h were 41.0 +/- 21.7 and 52.3 +/- 20.9 mumol l-1 respectively and for slow release theophylline at 0, 4 and 6 h 43.7 +/- 25.5, 50.9 +/- 23.0 and 51.7 +/- 26.4 mumol l-1 respectively. 3 Serum theophylline monitoring with slow release theophylline was performed in 70 patients with chronic lung disease. The initial dose was 250 mg administered 12 hourly. 4 The mean +/- s.d. steady state serum theophylline level achieved was 76.0 +/- 18.8 mumol l-1 and the mean +/- s.d. dose to produce this level was 9.4 +/ 2.3 mg kg-1 day-1. There was no correlation between dosage and serum theophylline level. 5 Sixty percent of patients required a dosage change for stabilization (375 to 1000 mg/day). Seventeen patients reported unwanted effects (nausea or tremor), which either settled quickly or resolved with dosage reduction. 6 Serum theophylline levels were obtained at different dosages in 44 patients and 18 patients demonstrated dose-dependent kinetics. 7 An initial dose of 500 mg/day is recommended and dosage increments should not exceed 125 mg/day with monitoring by serum theophylline levels.     

Steady-state pharmacokinetics and effects of a new once-daily, slow-release theophylline capsule preparation in asthma.

Plasma and saliva theophylline concentrations were measured in 21 asthmatic subjects receiving chronic oral therapy with a new sustained-release theophylline capsule (K1B Riker) given as a once daily dose, after titration to achieve a before-dose concentration of 8 mg l-1 or greater, or to the maximum dose of 1200 mg of theophylline daily. Plasma concentrations rose from a mean +/- s.d. minimum concentration (Cmin) of 7.9 +/- 2.3 mg l-1 to a mean maximum of 13.6 +/- 3.3 mg l-1 at a median time of 10 h after dosing. Saliva theophylline concentrations were closely related to the plasma theophylline concentration both between and within subjects with a mean saliva to plasma concentration ratio between subjects (S/P ratio) of 0.62 (+/- 0.05) and a mean within subject coefficient of variation of 8.2% (+/- 4.5%). There was a significant but small (10%) change in the mean S/P ratio during the dosing interval. Peak expiratory flow rate (PEFR) changed slightly but significantly during the dosing interval but forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) did not. The drug was well tolerated at the dose used (600-1200 mg once daily).     

Enhanced metabolism of mexiletine after phenytoin administration.

1 Unexpectedly low plasma concentrations of mexiletine were observed in three patients treated with mexiletine and concurrently taking phenytoin. 2 Six healthy volunteers were given a single oral dose of mexiletine (400 mg), before and after 1 week of phenytoin administration (300 mg/day). 3 The mean +/- s.d. area under the plasma mexiletine concentration-time curve decreased from 17.67 +/- 6.21 to 8.01 +/- 3.64 micrograms ml-1 h (P less than 0.003). 4 The mean +/- s.d. half-life of elimination of mexiletine decreased from 17.2 +/- 5.26 to 8.4 +/- 4.17 h (P less than 0.02) 5 The suggested mechanism of the interaction is hepatic mixed-function oxidase enzyme induction by phenytoin. 6 The interaction is likely to be clinically significant.     

Inability of ibuprofen to alter single dose phenytoin disposition.

The effect of ibuprofen treatment (1600 mg day-1 per os for 7 days) on single dose (300 mg per os) dispositional parameters of phenytoin (DPH) was evaluated in 10 healthy males. Ibuprofen slightly increased the free fraction of DPH from mean (+/- s.d.) value of 6.9 (+/- 0.7)% to 7.8 (+/- 0.3)% (P less than 0.01). DPH total clearance (CL/F) was not significantly changed going from a value of 0.027 (+/- 0.009) 1 h-1 kg-1 to 0.032 (+/- 0.014) 1 h-1 kg-1 (0.05 less than P less than 0.1). Intrinsic unbound DPH clearance (CLuint/F) was unaffected by ibuprofen treatment. Neither DPH's apparent volume of distribution (V/F) nor the apparent volume of distribution of unbound DPH (Vunb/F) were significantly altered by ibuprofen treatment. The slight changes in DPH plasma protein binding that are due to concurrent ibuprofen treatment in doses of 1600 mg day-1 are not likely to produce important changes in DPH dispositional parameters.     

Investigation of patients with abnormal response to warfarin.

In 55 patients in whom warfarin control had been satisfactory for at least 4 months, warfarin dose, plasma warfarin concentration and plasma clearance were measured. The mean dose to maintain the BCR (INR) between 2.3 and 3.3 was 5.1 +/- 2 mg day-1 (range 1.5-10 mg). Plasma warfarin concentrations and warfarin clearance were log-normally distributed with 95% confidence limits between 0.8 and 2.4 mg l-1 and 2.5 and 8.71 day-1 respectively. These confidence limits were used to construct algorithms which correctly predicted the cause of abnormal warfarin sensitivity in two patients and resistance in two further patients. These algorithms should help to identify the cause of abnormal warfarin responsiveness in the clinical setting.     

Anticonvulsant therapy and cortisol elimination.

The effect of anticonvulsant therapy on early morning concentration of cortisol in saliva and plasma was assessed in a group of epileptic patients receiving regular phenytoin medication and the results compared with those obtained from a group of normal subjects not receiving drug therapy. Values of cortisol in matched samples of plasma (331 +/- 23 nmol l-1, mean +/- s.e. mean, n = 6) and saliva (11.4 +/- 0.9 nmol l-1, mean +/- s.e. mean, n = 9) provided by epileptics did not differ significantly from those in the plasma (334 +/- 41 nmol l-1, mean +/- s.e. mean) and saliva (12.0 +/- 2.0 nmol-1, mean +/- s.e. mean) of healthy volunteers (n = 12). Six anticonvulsant-treated epileptics, together with six age and sex matched normal volunteers, each received intravenous dexamethasone (1 mg h-1) to determine the half-life of cortisol in plasma and saliva. In the anticonvulsant-treated group, the half-life of cortisol in plasma (73 +/- 5 min, mean +/- s.e. mean) and saliva (83 +/- 5 min, mean +/- s.e. mean) was reduced significantly (P less than 0.01 plasma, P less than 0.05 saliva) from that observed in healthy volunteers. In patients, the half life of cortisol and antipyrine showed a significant correlation (r2 = 0.75, P less than 0.05 plasma, r2 = 0.71, P less than 0.05 saliva). The antipyrine half-life in saliva was reduced significantly (P less than 0.02) and the antipyrine clearance rate, increased significantly (P less than 0.005) in the treated epileptic group, reflecting drug-induced microsomal enzyme production.(ABSTRACT TRUNCATED AT 250 WORDS)     

The influence of food on the pharmacokinetics of CGP 6140 (amocarzine) after oral administration of a 1200 mg single dose to patients with onchocerciasis.

Eleven male patients from Mali with Onchocerca volvulus infections received in random order a 1200 mg single oral dose of CGP 6140 after an overnight fast and after food intake. The concentrations of CGP 6140 and of its N-oxide metabolite, CGP 13231, were measured in plasma and urine. Mean (+/- s.d.) AUC CGP 6140 values were 67.0 +/- 10.8 mumol l-1 h in fed and 22.0 +/- 17.2 mumol l-1 h in fasting patients. The mean maximum concentrations (Cmax) in plasma +/- s.d. were 12.7 +/- 2.8 mumol l-1 in fed and 4.7 +/- 4.1 mumol l-1 in fasting patients. The median time to Cmax was 3 h in fed and 2 h in fasting patients. Mean (+/- s.d.) AUC of the N-oxide metabolite was 59.9 +/- 10.7 mumol l-1 h in fed and 23.4 +/- 16.2 mumol l-1 h in fasting patients. The urinary recovery was less than 0.5% of dose for CGP 6140 in both fed and fasting conditions. It was 30.1 +/- 11.5 and 11.4 +/- 8.0% of the dose for the N-oxide metabolite in fed and fasting conditions, respectively. Variability in plasma concentrations and urinary recovery of CGP 6140 and of the N-oxide metabolite was greater in fasted patients. The low solubility of CGP 6140 in aqueous solutions at neutral pH and its higher solubility at acidic pH might explain the increase in bioavailability after food intake. The administration of CGP 6140 after food intake is therefore recommended for an optimal systemic effect.     

Pharmacokinetics of a single dose of phenytoin in man measured by radioimmunoassay.

1. Serum concentrations of phenytoin were studied by radioimmunoassay in five normal volunteers following a single oral dose of phenytoin sodium (100 mg). 2. Two distinct peaks were found at 2.5-3.5 and 10-12 h after ingestion. Maximum serum concentrations ranged from 1.56 mug/ml. The mean plasma half-life of the drug under these conditions was 9.81 +/- 0.66 (s.e. mean) hours.     

The disposition of bupivacaine following a 72 h interpleural infusion in cholecystectomy patients.

The disposition of bupivacaine and degree of analgesia following a 72 h interpleural infusion was investigated in 12 adult patients undergoing elective cholecystectomy. The infusion regimen of an initial interpleural bolus dose of 20 ml of 0.5% bupivacaine HCl with adrenaline (1:200,000) followed by continuous infusion at a rate of 8 ml h-1 of 0.25% plain bupivacaine HCl was designed to achieve continuous post-operative pain relief for 72 h. In practice an additional bolus dose (identical to the first) administered 5 h after infusion commencement was required to achieve adequate pain relief on the first postoperative day. The mean measured steady-state plasma bupivacaine concentration was 2.1 mg l-1 (s.d. +/- 0.54, range 1.3-3.2 mg l-1). Disposition parameters for bupivacaine measured for the infusion were calculated by non-compartmental methods and compared with previous values obtained after single and multiple interpleural bolus dose administration. No statistically significant differences were noted and, in particular, the systemic clearance of bupivacaine (mean 10.2 l h-1 s.d +/- 3.0; range 6.3-16.0 1 h-1) remained unchanged following the long-term interpleural infusion. Analgesia was deemed satisfactory throughout the entire post-operative period.     

Atovaquone has no effect on the pharmacokinetics of phenytoin in healthy male volunteers

The potential pharmacokinetic interaction between atovaquone and phenytoin was investigated in 12 healthy male volunteers. Each volunteer received a single 600  mg oral dose of phenytoin in the two treatment periods. On one occasion phenytoin was taken alone and on the other after pre-treatment with 2000  mg atovaquone taken as two doses of 1000  mg as a microfluidized suspension. The mean (±s.d.) peak plasma concentrations ( C _max), apparent total clearance (CL/ F ) and terminal half-life ( t _½) for phenytoin when administered alone were 10.6(1.8)  mg l⁻¹, 24.3 (7.7)  ml min⁻¹ and 25(8)  h, respectively. When administered together with atovaquone, phenytoin C _max, CL/ F and t _½,z were 10.9 (2.0)  mg l⁻¹, 23.8  ml min⁻¹ and 24(6)  h, respectively. There were no statistically significant differences in any of these plasma pharmacokinetic parameters. There were also no statistically significant differences in the fraction of circulating drug not bound to plasma protein or urinary excretion of 5-hydroxyphenyl-phenyl-hydantoin. In conclusion, there was no effect of atovaquone on the pharmacokinetics of phenytoin or its major metabolite after a single dose.     

Mixed linear and non-linear disposition of lazabemide, a reversible and selective inhibitor of monoamine oxidase B.

1. Single oral doses (100-300 mg) and multiple oral doses (100-350 mg 12 hourly for 7 days) of lazabemide were administered to 35 young and 40 elderly healthy subjects. Plasma concentrations of unchanged drug were determined to study the dose-concentration relationship. 2. The elimination phase time course of lazabemide concentrations indicated concentration-dependent elimination after both single and multiple dosing. Nevertheless, maximum concentrations and areas under concentration-time curves increased almost proportionally with dose and accumulation after chronic dosing was less than a factor of 2; steady-state concentrations were achieved by the third day of dosing. The apparent half-life determining accumulation was approximately 8-9 h. 3. Drug absorption commenced rapidly after a dose; two components to the absorption process were detectable in young subjects possibly due to simultaneous administration of multiple tablets at the higher doses. 4. Observations after single and multiple dosing were described with a compartmental model allowing for parallel saturable (population mean +/- s.d.: maximum elimination rate Vmax/F: 2.8 +/- 1.4 mg h-1; concentration at half-maximum elimination Km: 36 +/- 19 micrograms l-1) and first-order (CL/F 16 +/- 3.8 l h-1) elimination pathways. No important difference between the young and the elderly subjects was noted in absorption or disposition parameters of lazabemide.     

The effect of carbamazepine on valproic acid disposition in adult volunteers.

1. Pharmacokinetic parameters for valproic acid (VPA) were determined before and following 2 weeks of carbamazepine (CBZ) administration in five healthy male volunteers. Mean VPA dosage was 16.4 mg kg-1 day-1. CBZ dosage was started at 100 mg twice daily and increased after 1 week to a total daily dose of 300 mg. 2. After CBZ administration, mean VPA plasma clearance increased from 0.90 +/- 0.18 s.d. to 1.26 +/- 0.24 l h-1 (P less than 0.05) as did clearance of free VPA (20.8 +/- 7.6 to 37.0 +/- 13.6 l h-1). Mean VPA elimination rate constant increased from 0.051 +/- 0.011 to 0.067 +/- 0.011 h-1 (P less than 0.05) after CBZ administration. 3. Mean area under the serum concentration vs time curve decreased from 675.0 +/- 130.5 to 475.7 +/- 75.7 mg l-1 h (P less than 0.05) after CBZ administration. Mean serum VPA half-life decreased from 14.0 +/- 2.4 to 10.6 +/- 1.4 h (P less than 0.05). Mean serum VPA trough concentrations decreased from 44.0 +/- 16.7 to 27.0 +/- 10.4 micrograms ml-1 (P less than 0.05). 4. A significant change was not observed in the mean VPA volume of distribution after CBZ coadministration suggesting that enzyme induction rather than a competition for plasma protein binding sites was involved in this interaction. 5. Despite the increased clearance of VPA, the urinary recovery of VPA or conjugate did not increase after CBZ administration.     

Pharmacokinetics of the trimethoprim-sulphamethoxazole combination in the elderly.

The pharmacokinetics of a co-trimoxazole preparation (Bactrim Forte) containing trimethoprim (TMP) 160 mg and sulphamethoxazole (SMZ) 800 mg were determined in six young adults (29.3 +/- 4.4 s.d. years) and six elderly people (78.6 +/- 6.6 s.d. years). Following oral administration of a single dose, the pharmacokinetic parameters of SMZ and its N4-acetylated metabolite (N4SMZ) were similar in both groups. However Cmax of TMP was greater (2.06 +/- 0.29 s.d. vs 1.57 +/- 0.32 s.d. mg l-1; P less than 0.01) and its area under the curve was larger (34.30 +/- 6.98 s.d. vs 23.87 +/- 3.82 s.d. mg l-1 h; P less than 0.001) in elderly people than in younger subjects. Total clearance (CL/F) of TMP normalized to body weight was not significantly different in the two groups. There was no significant difference in serum protein binding of TMP and SMZ between the two groups. Urinary excretion of TMP, SMZ and N4SMZ was reduced by about 50% in the elderly compared to the young subjects. Renal clearance of TMP was significantly lower in the elderly group (19 +/- 10 s.d. vs 55 +/- 14 s.d. ml h-1 kg-1; P less than 0.001). Renal clearance of SMZ was not significantly different in the two groups. A study of plasma concentrations of TMP, SMZ and N4SMZ during continuous dosing in seven elderly patients treated for urinary or respiratory infections showed that steady state was reached after 3 days of treatment and that plasma drug concentrations were about two to three times higher than those observed after a single dose.     

Effects of cimetidine and ranitidine on the pharmacokinetics of quinine.

The pharmacokinetics of orally administered quinine were determined in six normal volunteers before and after a 7-day course of cimetidine (1 g day-1) or ranitidine (300 mg day-1). Peak plasma quinine concentration and the time of peak concentration were not altered after cimetidine or ranitidine pretreatment. After cimetidine pretreatment there was a significant reduction in the apparent oral clearance of quinine, from 0.182 +/- 0.063 (mean +/- s.d.) to 0.133 +/- 0.055 1 h-1 kg-1 (P less than 0.05). This was reflected in a 49% (range 17 to 90%) increase in the mean elimination half-life from 7.6 +/- 1.3 to 11.3 +/- 3.7 h (P less than 0.05). In contrast to cimetidine, ranitidine had no significant effect on the clearance or half-life of quinine. The apparent interaction between quinine and cimetidine may have therapeutic implications. Special care should be taken in patients taking these two common drugs concomitantly. Additionally, to avoid unnecessary risks due to drug interaction, the use of ranitidine may be preferable in the patients in whom it is desirable to administer an H2-receptor antagonist together with quinine.     

Moclobemide excretion in human breast milk.

1. Six lactating white women, aged 24-36 years, received a single oral dose of 300 mg moclobemide, between 09.00 h and 11.00 h, 3 to 5 days after the delivery of a full term neonate. 2. Complete milk collections were obtained before, 3, 6, 9, 12 and 24 h after drug administration by means of a breast pump. Venous blood samples were drawn before, and 0.5, 1, 3, 4.5, 6, 9, 12, 24 h post-dosing. 3. Moclobemide, and its major metabolite (Ro 12-8095) were measured in milk and plasma samples using h.p.l.c. The active metabolite (Ro 12-5637) could only be detected in plasma. 4. Moclobemide and its metabolites were not detectable in 24 h plasma samples. Cmax, tmax and t1/2 for moclobemide were (mean +/- s.d.) 2.70 +/- 1.24 mg l-1, 2.03 +/- 1.19 h and 2.26 +/- 0.26 h, respectively. 5. The concentrations of moclobemide and Ro 12-8095 in milk were highest at 3 h after drug administration and the drug and metabolite were not detectable after 12 h. Ro 12-5637 was not detected in any milk sample. The percentages of the dose excreted as moclobemide and Ro 12-8095 were (mean +/- s.d.) 0.057 +/- 0.020% and 0.031 +/- 0.011%, respectively. An average 3.5 kg breast-fed neonate would therefore be exposed to only a 0.05 mg kg-1 moclobemide dose (approximately 1% of the maternal dose on the mg kg-1 basis). The low amount of moclobemide excreted into breast milk is unlikely to be hazardous to suckling infants.     

Pharmacodynamics of lazabemide, a reversible and selective inhibitor of monoamine oxidase B.

1. The inhibition of monoamine oxidase B (MAO-B) by lazabemide was measured in platelets collected from 35 young (19-36 years) and 40 older (60-78 years) healthy volunteers after single (100-300 mg) and multiple (100-350 mg twice daily) oral doses respectively. 2. The relationship of the effect with plasma concentrations of the MAO-B inhibitor was defined by a sigmoid Imax-model using either a parametric or semi-parametric method for predicting plasma drug concentrations. Population parameter estimates were obtained by the expectation maximization method and a standard two-stage method. 3. At the lowest dose platelet MAO-B activity was almost completely inhibited for around 20 h. No time delay between plasma drug concentration and resulting inhibition of platelet MAO-B occurred. Low concentrations of the inhibitor produced 50% of maximum inhibition (IC50, estimates for population mean +/- s.d.: 0.48 +/- 0.89 microgram l-1 for young and 1.5 +/- 2.3 micrograms l-1 for elderly subjects). The maximum extent of enzyme inhibition attributable to lazabemide (Imax) was 94 +/- 5.1% and 96 +/- 4.5% in the young and older populations. There was no correlation between age and either Imax or IC50. 4. Model parameters describing the interaction of lazabemide with the enzyme did not change over the treatment period of 7 days.     

Treatment of quinine overdosage with repeated oral charcoal.

In five symptomatic patients with acute quinine poisoning the mean admission plasma concentration was 11.1 mg l-1. After treatment with repeated oral charcoal 50 g 4 hourly, plasma quinine concentrations fell rapidly with a mean half-life of 8.1 +/- 1.1 h (s.d.) compared with more than 24 h in a previous report in similarly poisoned patients. The visual impairment which was expected in a patient with cardiotoxicity and a plasma quinine concentration of 12.6 mg l-1 did not occur, but late treatment with charcoal was of no obvious benefit in another patient who was already blind. Repeated oral charcoal has been shown to increase the rate of elimination of a therapeutic dose of quinine in healthy volunteers. It appears to be the only practical means of enhancing the removal of this drug after overdosage and should reduce the risk of potentially disastrous complications.