The effect of rifampicin on the blood concentration-time curve of propranolol at steady-state following oral administration of 120 mg every 8 h was investigated in six normal, young, male subjects. After an initial 2 week dosing period, all individuals additionally received 600 mg rifampicin daily for 3 weeks followed by a 4 week period during which again only the propranolol was given. In four of the subjects the effects of 900 and 1200 mg rifampicin daily was also studied. Changes in disposition were assessed by estimation of propranolol's oral clearance and elimination half-life during the dosage interval. Rifampicin (600 mg/day) caused a large increase in propranolol's oral clearance (35.7 + 16.3 vs 96.1 + 26.9 ml min-m kg-', mean + s.d.), but neither the elimination half-life nor extent of plasma binding were affected. Increasing the daily dosage to 900 and 1200 mg did not cause any additional changes in oral clearance. Four weeks after discontinuing rifampicin, propranolol's oral clearance had essentially returned to its pre-induction level. The oral clearance of propranolol was significantly smaller (89.5 + 14.4%) during the dosage interval immediately after administration of the last rifampicin dose than the value measured 24 h later. The findings are consistent with rifampicin causing induction of the drug metabolizing enzymes responsible for propranolol's biotransformation. The marked reduction in the steady-state propranolol blood concentration that results from chronic rifampicin administration would be expected to result in a significant change in clinical effectiveness of the ,/-adrenoceptor blocker when the two drugs are used concurrently.
1 The effect of dose (100 mg, 250 mg, 500 mg, 750 mg and 1000 mg) on the glucuronidation and sulphation of diflunisal was studied in six healthy volunteers. 2 Total urinary recovery ranged from 78.9 ± 11.9% to 91.5 ± 18.7% of the administered dose. Urinary recovery (normalized for total urinary recovery) of diflunisal sulphate (DS) significantly increased with dose from 9.3 ± 3.7% to 18.1 ± 4.8%.3 Normalized urinary recovery for diflunisal phenolic glucuronide (DPG) was unaffected by dose (range: 30.6 ± 3.8% to 40.6 ± 6.6%). Normalized urinary recovery for the acyl glucuronide (DAG) significantly decreased from 52.3 ± 4.6% to 40.2 ± 3.4% as the dose increased.4 Total plasma clearance of diflunisal significantly decreased from 14.4 ± 1.4 ml min-lto 8.7 ± 1.4 ml min-t as the dose increased from 100 mg to 750 mg. A further increase in dose to 1000 mg resulted in an unexplained increase in total plasma clearance to 10.3 ± 1.8 ml * -1 mmn 5 Dose-dependent plasma clearance of diflunisal was caused mainly by saturation of the formation of DAG, whereas the formation of DS and DPG were relatively unaffected by dose.
1 All /8-adrenergic receptor blockers that require metabolism prior to elimination are potentially subject to drug interactions due to enzyme induction. However, data is only available in man for propranolol, metoprolol and alprenolol. 2 Cross-sectional population studies suggest that environmental factors, such as smoking in the young, are able to influence the oral clearance of propranolol. 3 Long-term studies comparing within-subject clearances of metoprolol, alprenolol and propranolol before and after rifampicin and pentobarbitone, indicate that oral clearance is increased by 50%-500%. 4 Inducing agents can influence intrinsic clearance, liver blood flow, and protein binding in addition to drug metabolising ability, indicating that changes in pharmacokinetic disposition may be complex. 5 Enzyme induction exhibits both dose and time dependency relationships. 6 The maximal extent of enzyme induction is similar between subjects. The range of intersubject variation in drug metabolism is similar before and after induction. 7 The reduction in steady-state /8-adrenergic receptor drug concentration following enzyme induction is sufficiently large that an altered pharmacodynamic response would be expected if no dosage modification is made.
1 The single (250 and 500 mg) and multiple dose (250 and 500 mg twice daily for 15 days) pharmacokinetics of diflunisal were compared in young volunteers. 2 The plasma clearance of diflunisal was lowered significantly after multiple dose administration (5.2 ± 1.2 and 4.2 ± 0.7 ml min-' for the 250 and 500 mg twice daily regimens, respectively) as compared with single dose administration (11.4 ± 3.1 and 9.9 + 2.0 ml min-' for the 250 and 500 mg single doses, respectively).3 The partial metabolic clearances of diflunisal by acyl and phenolic glucuronide formation were lowered significantly (> 50%) after multiple dose administration. 4 The urinary recovery of diflunisal sulphate increased as a function of dose: 6.1 ± 2.8 and 9.1 ± 3.5% following the 250 and 500 mg single dose, respectively, and 10.9 ± 3.1 and 15.9 ± 3.6% following the 250 and 500 mg twice daily regimens. The partial metabolic clearance of diflunisal by sulphate conjugation was unchanged following multiple dose administration. 5 The plasma protein binding of diflunisal was concentration-dependent. Analysis of unbound plasma clearances of diflunisal showed that its total plasma clearance following 500 mg twice daily was affected by both saturable glucuronidation and concentrationdependent plasma binding.
Comparing modified‐release formulations can be difficult using current bioequivalence criteria. Two 60‐mg‐once‐daily nifedipine formulations are deemed bioequivalent in Canada. This study examined the validity of the assumption that these interchangeable, but different, delivery technologies are therapeutically equivalent in maintaining systolic blood pressure (SBP) control throughout the entire dosing interval. We used 24‐h Ambulatory Blood Pressure Monitoring to objectively examine whether formulation switches changed population SBP >2 mmHg (reflecting 6% increased stroke mortality) and in what proportion of patients SBP changed ≥6 mmHg (risking unnecessary therapeutic alterations). When 20 patients, previously receiving 60‐mg‐once‐daily Nifedipine‐GITS, were switched to Mylan‐Nifedipine‐XL, population‐mean ± SE 24‐h SBP increased 3 ± 1.1 mmHg (P = 0.0173) and 8‐h nocturnal SBP increased 4 ± 1.6 mmHg (P = 0.0098). Thus, interchange of nifedipine formulations can affect therapeutic consistency. These data support existing calls to improve criteria for establishing bioequivalence between formulations employing differing modified‐release technologies.
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