Welker H A
F. Hoffmann-La Roche Ltd, Basel, Switzerland.
J Pharm Pharmacol. 1998 Sep;50(9):983-7. doi: 10.1111/j.2042-7158.1998.tb06912.x.
Mibefradil is a single-enantiomer calcium antagonist belonging to a new class, the tetralol derivatives. The recommended doses for treatment of hypertension and chronic stable angina pectoris are 50 or 100 mg. Mibefradil is metabolized via parallel pathways of esterase-catalysed hydrolysis and cytochrome P450 3A4-mediated oxidation. Mibefradil also inhibits cytochrome P450 3A4 and consequently inhibits its own metabolism, a property illustrated by three studies performed early in the drug's development. After single intravenous doses of 2.5 to 80 mg to healthy male subjects, pharmacokinetics are linear. At the representative 40 mg intravenous dose mean pharmacokinetic parameters were clearance 241 +/- 76 mL min(-1), terminal exponential half-life 15.0 h and volume of distribution at steady state 213 L. After single oral doses of 10 to 320 mg, reduced first-pass metabolism occurs with increasing dose. This effect is accompanied by increasing absolute bioavailability as the dose is increased. In an oral multiple-dose study of healthy male volunteers mibefradil doses of 100, 150 or 250 mg (from tablets) were administered once daily for 28 days. Reduction of the first-pass effect was noted, although the data suggested that a maximum was reached for doses of 150 mg or more. In a study of the effect of hypertension on mibefradil pharmacokinetics, 12 patients received oral mibefradil once daily at doses of 50, 100, 150, or 200 mg in 100 mL orange juice for 8 days. Steady state was reached within 3 days and accumulation generally ranged from three- to sevenfold. Single-dose non-linearity was observed in the first-pass effect, although for multiple dosing oral clearance values were dose-independent and lower than for single doses. After multiple dosing at the recommended dosage of 50 and 100 mg once daily, oral clearance of mibefradil stabilizes to approximately the same value for both doses. Hence, the single-dose non-linearity has little clinical relevance but demonstrates the self-inhibition of metabolism seen with mibefradil. Studies so far suggest that self-inhibition of its oxidative metabolic pathway leads to a low clearance and long half-life, enabling once-daily dosing and conferring low intra- and inter-patient variability in pharmacokinetics.
米贝拉地尔是一种单一对映体钙拮抗剂，属于一类新型药物，即四氢萘酚衍生物。治疗高血压和慢性稳定型心绞痛的推荐剂量为50或100毫克。米贝拉地尔通过酯酶催化水解和细胞色素P450 3A4介导的氧化这两条平行途径进行代谢。米贝拉地尔还抑制细胞色素P450 3A4，从而抑制自身代谢，药物研发早期进行的三项研究证明了这一特性。对健康男性受试者单次静脉注射2.5至80毫克后，药代动力学呈线性。在代表性的40毫克静脉注射剂量下，平均药代动力学参数为清除率241±76毫升/分钟，终末指数半衰期15.0小时，稳态分布容积213升。单次口服10至320毫克后，首过代谢随剂量增加而降低。随着剂量增加，这种效应伴随着绝对生物利用度的增加。在一项健康男性志愿者的口服多剂量研究中，米贝拉地尔剂量为100、150或250毫克（片剂），每天给药一次，共28天。观察到首过效应降低，尽管数据表明150毫克或更高剂量达到了最大值。在一项高血压对米贝拉地尔药代动力学影响的研究中，12名患者每天口服一次米贝拉地尔，剂量为50、100、150或200毫克，溶于100毫升橙汁中，共8天。3天内达到稳态，蓄积一般在三到七倍之间。在首过效应中观察到单剂量非线性，尽管对于多剂量给药，口服清除率值与剂量无关且低于单剂量。按照推荐剂量每天50和100毫克多次给药后，米贝拉地尔的口服清除率在两种剂量下均稳定在大致相同的值。因此，单剂量非线性在临床上几乎没有相关性，但证明了米贝拉地尔存在的代谢自抑制现象。迄今为止的研究表明，其氧化代谢途径的自抑制导致清除率低和半衰期长，使得每日给药一次成为可能，并在药代动力学方面赋予患者体内和患者间较低的变异性。
