No abstract

1. The effect of age on the pharmacokinetics of levodopa administered alone and in the presence of carbidopa was investigated in young and elderly healthy volunteers. 2. The plasma clearance of levodopa following intravenous administration of 50 mg was 14.2 +/‐ 2.8 (s.d.) ml min‐1 kg‐1 in the elderly compared with 23.4 +/‐ 4.1 ml min‐1 kg‐1 in the young (P less than 0.01) which resulted in a 49% greater area under the plasma concentration‐time curve (AUC) in the older subjects (P less than 0.01). The volume of distribution (Vss) was lower in the elderly (1.01 +/‐ 0.29 l kg‐1) than in the young (1.65 +/‐ 0.39 l kg‐1) (P less than 0.002). 3. Following oral administration of 250 mg of levodopa the AUC was 2512 +/‐ 588 ng ml‐1h in the elderly compared with 1056 +/‐ 282 ng ml‐1h in the young (P less than 0.002). Cmax was also significantly greater in the elderly (P less than 0.05). The bioavailability of levodopa was significantly greater in the elderly (0.63 +/‐ 0.12 compared with 0.41 +/‐ 0.16, P less than 0.01). 4. In the presence of carbidopa, the plasma clearance of intravenous levodopa (50 mg) was reduced in both age groups but remained lower in the elderly (5.8 +/‐ 0.9 ml min‐1 kg‐1 compared with 9.3 +/‐ 1.0 ml min‐1 kg‐1; P less than 0.01). This resulted in a 54% greater AUC in the older subjects (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Oral administration of nifedipine (20 and 30 mg tablets) to six volunteers was associated with a bioavailability of 0.43 and the presence of its nitropyridine analogue in the plasma. This metabolite was present in only trace amounts in samples taken from the same volunteers following i.v. administration of nifedipine. The peak plasma concentrations and area under the plasma concentration‐time curve suggest that the nitropyridine analogue is a major, first pass, metabolite of nifedipine.

1. Simultaneous radioisotopic (99Tc‐DTPA) gastric emptying measurements and paracetamol pharmacokinetic studies were performed in eight healthy male volunteers with and without levodopa (125 mg orally). 2. In the absence of levodopa gamma camera imaging showed rapid mono or biexponential emptying in all subjects and the plasma concentration‐ time curves for paracetamol displayed a single major peak. 3. In the presence of levodopa the time to 90% emptying was prolonged from 32 +/‐ 24 min to 81 +/‐ 20 min (P less than 0.01). Gastric emptying was interrupted by a plateau phase in six subjects and this pattern of emptying was associated with double peaks in the plasma concentration‐ time curves of both levodopa and paracetamol. The time to the end of the plateau phase of emptying correlated with the time to the trough plasma concentrations of paracetamol and levodopa. 4. There was excellent agreement between the plasma concentration‐time curves of levodopa and paracetamol, i.e. time to initial peak, r = 0.946, P less than 0.001; time to trough concentration r = 0.943, P less than 0.01; time to second peak r = 0.974, P less than 0.001. 5. The results indicate that levodopa inhibits gastric emptying and thus influences its own absorption. Temporary inhibition of gastric emptying by levodopa (or a metabolite) is the cause of the multiple plasma peaks commonly observed following oral levodopa.

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 ml 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 (AUC) (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).(ABSTRACT TRUNCATED AT 250 WORDS)

Simultaneous measurements of the clearance rates of technetium 99m diethylenetriaminepentaacetic acid (99mTc-DTPA) and chronium 51 ethylenediaminetetraacetic acid (51Cr-EDTA) were performed in 30 patients with a range of renal function (glomerular filtration rates between 9 and 120 ml/min). Using multiple blood samples, the two clearance values correlated well (r = 0.991, standard error 3.9 ml/min), but DTPA clearance was systematically higher by 7.6%. For each radiopharmaceutical, an equation was derived to correct clearance values obtained using only plasma samples taken at 2 and 4 h for the systematic error inherent in this technique compared with analysis of the complete plasma concentration-time curve. The root mean square error remaining after application of these equations was 1.9 ml/min for both the EDTA and DTPA data. The corresponding errors obtained using the equation derived by Brochner-Mortensen for EDTA plasma clearance were 2.2 ml/min and 1.9 ml/min, respectively, these values were not significantly different from those obtained using the equations derived in this study.

Quercetin, a flavonoid present in various fruits, is a potent in vitro inhibitor of CYP3A. Its role in the reported interaction between grapefruit juice and nifedipine has been determined in vivo in humans. Eight healthy volunteers were given in random order 10 mg nifedipine orally, either alone or with 200 ml double strength grapefruit juice, or with 400 mg quercetin. The area under the plasma concentration-time curve (AUC) for nifedipine with grapefruit juice (mean 320 ng ml-' h) was increased significantly (P < 0.01) compared with the AUC when nifedipine was given alone (mean 218 ng ml-1 h).The time to peak plasma concentration for nifedipine with grapefruit juice (1.5 h) was also increased (P < 0.05) compared with control (0.5 h) suggesting delayed absorption. Although quercetin delayed the time to peak nifedipine concentration (1.3 h) it did not alter the AUC of either the parent drug (mean 209 ng ml-' h) or its first-pass metabolite.The results suggest that quercetin does not contribute to the effects of grapefruit juice (which contains <10 mg of quercetin 200 ml-') on the metabolism of nifedipine. Oral doses of quercetin, similar to those possible from the ingestion of other fruits such as strawberries, do not produce in vivo inhibition of CYP3A mediated metabolism of nifedipine.

1 The effects of age on the pharmacology of nifedipine were investigated in 11 young and six elderly normotensive volunteers. 2 Following 2.5 mg of nifedipine i.v. the plasma clearance of nifedipine was 348 ± 83 (s.d.) ml min-1 in the elderly compared with 519 ± 125 ml min'-in the young (P < 0.05) and the AUC in the elderly was significantly greater at 125 ± 28 ng mlF-I h compared with 83.9 ± 19 ng ml-' h (P < 0.05). The V1, was similar in both age groups.3 Following 10 mg oral sustained release nifedipine the AUC was 281 ± 64 ng ml-l h in the elderly compared with 136 ± 56 ng ml-' h in the young (P < 0.002) and Cmax in the elderly was significantly greater at 36.8 ± 11.8 ng ml-' compared with 22.3 ± 5.8 ng ml-' (P < 0.05). The trend towards an increased bioavailability in elderly subjects (36%) was supported by a significantly lower nitropyridine metabolite/nifedipine ratio in the elderly. 4 Absorption rate limited kinetics of the sustained release formulation were indicated by the prolonged tv2 compared with i.v. administration. In the elderly t½2 (oral) was significantly greater than in the young (elderly 6.7 ± 2.2 h, young 3.8 ± 1.4 h, P < 0.05). 5 Haemodynamic changes in the young were confined to a tachycardia following i.v. administration. In the elderly, supine BP fell significantly following both oral and i.v. nifedipine while the heart rate remained unchanged. 6 The results suggest that a reduction in first pass metabolism and clearance of nifedipine and impaired baroreceptor function in the elderly may both contribute to its increased hypotensive effect in this age group.