FACTORS AFFECTING THE ABSOLUTE BIOAVAILABILITY OF NIFEDIPINE

1 Nifedipine was administered to eight volunteers (seven Caucasian, one East Asian of Chinese origin) as a single 10 mg capsule orally and as 2.5 mg intravenously. The pharmacokinetics were determined under fasting conditions and following 200 mi double strength grapefruit juice taken orally both 2 h before and at the time of dosing. 2 In a separate study, the pharmacokinetics of nifedipine were defined in eight South Asian volunteers (with both parents originating from the Indian subcontinent) following 10 mg nifedipine orally and 2.5 mg intravenously. 3 The administration of grapefruit juice did not alter the pharmacokinetics of intravenous nifedipine, but resulted in a significantly increased area under the plasma concentration-time curve (AUG) (191 +/- 59 c.f. 301 +/- 95 ng ml(-1) h, P < 0.05) and bioavailability (0.63 +/- 0.18 c.f: 0.86 +/- 0.15, P < 0.05) following oral nifedipine, The elimination half-life was unchanged by administration of grapefruit juice and there was no evidence of decreased formation of the nitropyridine first-pass metabolite. 4 The AUC of nifedipine after intravenous administration was significantly higher in South Asian subjects than in Caucasians (146 +/- 39 c.f. 74 +/- 18 ng ml(-1) h, P < 0.002). This was due to a lower systemic clearance in the South Asians which was 50% of that in the Caucasians. The half-life was markedly prolonged in South Asians (4.1 +/- 1.9 c.f: 1.7 +/- 0.5 h, P < 0.002). 5 The oral administration of nifedipine resulted in a significantly higher AUC of nifedipine in the South Asian compared with the Caucasian volunteers (402 +/- 198 c.f: 187 +/- 62 ng ml(-1) h, P < 0.05). However, the bioavailability was similar at 0.64, suggesting that reduced systemic clearance is the cause of the differences in AUCs observed with both routes of administration. Consistent with this, the elimination half-life was prolonged in the Asians (5.3 +/- 1.5 c.f: 2.6 +/- 1.1 h, P < 0.01). The AUC of the nitropyridine first-pass metabolite was similar in the two groups. 6 These data on the bioavailability and systemic clearance of nifedipine indicate that intestinal and hepatic CYP3A activities may be influenced independently by environmental and/or genetic factors.