Effects of cimetidine on carbamazepine auto‐ and hetero‐induction in man.

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114

1 Oxcarbazepine (OXC), the 10-keto analogue of carbamazepine (CBZ), has similar anticonvulsant efficacy and possibly improved patient tolerability. Unlike CBZ, it is metabolised by reduction and may not induce hepatic monooxygenase enzymes. 2 Serum concentrations of OXC and its active metabolite 10-OH-carbazepine (10-OH-CZ) were followed after a single 300 mg dose and during and after 300 mg OXC twice daily for 29 doses in eight healthy male volunteers. 3 Antipyrine metabolism, urinary 6-,-hydroxycortisol excretion, sex hormone binding globulin (SHBG) levels and circulating androgens were measured as indices of hepatic enzyme induction before, during and after treatment with OXC. 4 Elimination half-lives (mean ± s.e. mean) of 10-OH-CZ were unaltered by 2 weeks' therapy with OXC (before 11.3 ± 1.1 h; after 13.9 ± 3 h). Trough plasma concentrations of 10-OH-CZ at steady-state (31 ± 2.2 ,umol 1-1) were higher than predicted (16.5 + 4 ,umol 1-1).5 Antipyrine metabolism, urinary 6-13-hydroxycortisol excretion, SHBG levels and circulating androgens were unaltered by treatment with OXC. 6 OXC (600 mg daily) does not induce hepatic monooxygenase enzymes and so is likely to have more predictable dose-concentration relationships and to produce fewer physiological and pharmacological interactions than CBZ.

Section: Assaysmentioning

confidence: 99%

Lack of enzyme induction with oxcarbazepine (600 mg daily) in healthy subjects.

Larkin

Mckee

Forrest

et al. 1991

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114

“…Cognitive function tests, as previously described (Gillham et al, 1988) (Macphee et al, 1984). Inter-assay coefficients of variation for CBZ at 1.5, 6 and 12 mg 1-1 were 3.1, 3.0 and 4.8%, respectively.…”

Section: Protocolmentioning

confidence: 99%

Monotherapy with conventional and controlled‐release carbamazepine: a double‐blind, double‐dummy comparison in epileptic patients.

Mckee

Blacklaw

Butler

et al. 1991

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1 Twenty-one epileptic patients completed a double-blind, double-dummy, random order, crossover comparison of conventional carbamazepine (CBZ, Tegretol, CibaGeigy) with a new controlled-release formulation (CBZ-CR, Tegretol Retard). All participants were stabilised on maximally tolerated doses of CBZ as monotherapy (one twice daily, twelve three times daily, eight four times daily). Each preparation was taken with a matched placebo of the other for 4 weeks. 2 Peak serum CBZ concentrations (mean ± s.e. mean) were lower (CBZ 11.4 ± 0.4 mg 1-1; CBZ-CR 10.4 ± 0.5 mg 1-1; P < 0.01) and times to peak longer (CBZ 3.6 ± 0.5 h, CBZ-CR 5.2 ± 0.7 h, P < 0.01) during CBZ-CR treatment. Mean CBZ concentrations, however, were also slightly reduced with the new formulation (CBZ 9.9 ± 0.3 mg I-1; CBZ-CR 9.1 ± 0.5 mg 1-1, P < 0.05) and this was associated with greater seizure frequency (CBZ 2.8 ± 1.2, CBZ-CR 3.8 ± 0.9; P < 0.05) during the CBZ-CR treatment phase.3 Diurnal fluctuations (CBZ 41 ± 3%, CBZ-CR 28 ± 2%, P < 0.01) and variations (CBZ 53 ± 5%, CBZ-CR 33 ± 3%; P < 0.01) in serum CBZ concentration were substantially less with CBZ-CR and were similar to those calculated during a 6 or 8 hourly dosage interval with conventional CBZ (fluctuation 33 ± 3%, variation 42 + 5%). 4 Trough serum concentrations of the active metabolite CBZ 10,11 epoxide (CBZ-E)were lower on CBZ-CR (P < 0.05) than with conventional CBZ but no differences in peak or mean CBZ-E concentrations nor times to peak were found. Similar variations and fluctuations in CBZ-E concentrations were obtained with both formulations.5 Reaction times were longer (P < 0.05) and subjective side-effect scores higher (P < 0.05) shortly after dosing with conventional CBZ. 6 Blind patient preference significantly favoured CBZ-CR (fifteen CBZ-CR, two CBZ, four neither; P < 0.01). 7 CBZ-CR is a pharmacokinetically attractive method of administering CBZ and produces fewer subjective side-effects. However, the new formulation resulted in lower mean CBZ concentrations when given in the same total daily dose as the conventional preparation and may be less effective unless the dose is modified.

“…Antipyrine was assayed by high pressure liquid chromatography (Macphee et al, 1984). The first-order elimination rate constant (k) was calculated from the concentration time curve using the method of least square regression analysis assuming monoexponential decay.…”

Section: Methodsmentioning

confidence: 99%

Antipyrine metabolism in acute hepatic porphyria in relapse and remission.

Birnie

Mccoll

Thompson

et al. 1987

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Antipyrine kinetics following a single oral dose were obtained in porphyric patients in attack and in remission and in controls. The clearance of antipyrine was significantly lower during an acute porphyric attack (median: 0.34 ml min‐1 kg‐1; range: 0.1‐0.71, P less than 0.05) than in patients in remission (median: 0.53 ml min‐1 kg‐1; range: 0.28‐0.87) or controls (median: 0.52 ml min‐1 kg‐1; range: 0.32‐ 0.93). There was a significant negative correlation between weight‐ adjusted antipyrine clearance and the urinary excretion of the porphyrin precursors, delta‐aminolaevulinic acid (r = 0.86, P less than 0.001) and porphobilinogen (r = 0.82, P less than 0.002). These data suggest that the more severe the porphyric attack, the greater the impairment of hepatic monooxygenase activity.