Stereoselective pharmacokinetics of cisapride in healthy volunteers and the effect of repeated administration of grapefruit juice

AIMS: To determine whether the pharmacokinetics of cisapride and its interaction with grapefruit juice are stereoselective. METHODS: The study was a randomized, two-phase cross over design with a washout period of 2 weeks. Ten healthy volunteers were pretreated with either water or 200 ml double strength grapefruit juice three times a day for 2 days. On the 3rd each subject ingested a single 10 mg dose of rac-cisapride tablet. Double strength grapefruit juice (200 ml) or water was administered during cisapride dosing and 0.5 and 1.5 h thereafter. Blood samples were collected before and for 32 h after cisapride administration. Plasma concentrations of cisapride enantiomers were measured by a chiral h.p.l.c. method. A standard 12-lead ECG was recorded before cisapride administration (baseline) and 2, 5, 8, and 12 h later. RESULTS: This study showed that cisapride pharmacokinetics are stereoselective. In control (water treated) subjects, the mean Cmax (30 +/- 13.6 ng ml-1; P = 0.0008) and AUC(0, infinity) (201 +/- 161 ng ml-1 h; P = 0.029) of (-)-cisapride were significantly higher than the Cmax (10.5 +/- 3.4 ng ml-1) and AUC(0, infinity) (70 +/- 51.5 ng ml-1 h) of (+)-cisapride. There was no marked difference in elimination half-life between (-)-cisapride (4.7 +/- 2.7 h) and (+)-cisapride (4.8 +/- 3 h). Compared with the water treated group, grapefruit juice significantly increased the mean Cmax of (-)-cisapride from 30 +/- 13.6-55.5 +/- 18 ng ml-1 (95% CI on mean difference, -33, -17; P = 0.00005) and of (+)-cisapride from 10.5 +/- 3.4 to 18.4 +/- 6.2 ng ml-1 (95% CI on mean difference, -11.8, -3.9, P = 0.00015). The mean AUC(0, infinity) of (-)-cisapride was increased from 201 +/- 161 to 521.6 +/- 303 ng ml-1 h (95% CI on mean difference, -439, -202; P = 0.0002) and that of (+)-cisapride from 70 +/- 51.5 to 170 +/- 91 ng ml-1 h (95% CI on mean difference, -143, -53; P = 0.0005). The tmax was also significantly increased for both enantiomers (from 1.35 to 2.8 h for (-)-cisapride and from 1.75 to 2.9 h for (+)-cisapride in the control and grapefruit juice group, respectively; P < 0.05). The t(1/2) of (-)-cisapride was significantly increased by grapefruit juice, while this change did not reach significant level for (+)-cisapride. The proportion of pharmacokinetic changes brought about by grapefruit juice was similar for both enantiomers, suggesting non-stereoselective interaction. We found no significant difference in mean QTc intervals between the water and grapefruit juice treated groups. CONCLUSIONS: The pharmacokinetics of cisapride is stereoselective. Grapefruit juice elevates plasma concentrations of both (-)- and (+)-cisapride, probably through inhibition of CYP3A in the intestine. At present, there are no data on whether the enantiomers exhibit stereoselective pharmacodynamic actions. If they do, determination of plasma concentrations of the individual enantiomers as opposed to those of racemic cisapride may better predict the degree of drug interaction, cardiac safety and prokinetic efficacy of cisapride.     

The effect of food and bile acid administration on the relative bioavailability of cyclosporin.

1. The relative bioavailability of cyclosporin was studied in 11 healthy volunteers after single oral capsule doses of cyclosporin on three separate occasions; fasting, with breakfast and with breakfast together with bile acid tablets (400 mg of cholic acid and 100 mg of dehydrocholic acid). 2. There was a significant increase in the area under the blood concentration vs time curve (AUC) of cyclosporin when the drug was taken together with breakfast and bile acid tablets (9078 ng ml-1 h) as compared with breakfast alone (7453 ng ml-1 h, P less than 0.05) or fasting conditions (7283 ng ml-1 h, P less than 0.01). 3. A blood drug concentration vs time curve displaying two peaks was present in 9/11 subjects when cyclosporin was taken with breakfast or with breakfast and bile acid tablets, but only one peak was present when cyclosporin was taken during fasting, suggesting an enterohepatic circulation of cyclosporin or a second absorption phase after the meal. 4. In a separate study, 12 h trough blood cyclosporin concentrations were measured before and after 1 week of bile acid treatment in 19 clinically stable, out-patient transplant recipients who were treated with oral cyclosporin solution (mean dose 2.0 mg kg-1 twice daily). The administration of cyclosporin was not standardized with regard to food intake. There was no significant difference in the blood concentrations of cyclosporin before and after bile acid treatment (114 +/- 38 ng ml-1 vs 121 +/- 38 ng ml-1).(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of biological activities of two low molecular weight heparins in 10 healthy volunteers.

1. Low molecular weight heparins (LMWHs) are produced by different depolymerization processes and may therefore differ with respect to their pharmacokinetic properties. 2. We designed a single dose, randomized cross-over study in 10 healthy volunteers to compare the 24 h pharmacokinetics of two LMWHs, reviparin and enoxaparin, which have been previously shown to be clinically equivalent in terms of post-operative deep vein thrombosis prevention, despite significant differences in their in vivo biological activity. The two LMWHs were subcutaneously administered at the same dosages that are used in clinical studies: 4250 anti-Xa iu for reviparin and 40 mg for enoxaparin which have similar in vitro anti-Xa activities. 3. The overall 24 h profiles of the plasma anti-Xa and anti-thrombin activities were similar for reviparin and enoxaparin. The Amax and the AUC(0, 24h) of plasma anti-Xa activity after reviparin administration were both slightly but significantly lower than those observed after enoxaparin administration (difference between treatments of 0.03 95% CI[0.01-0.05] iu ml-1 h and 0.56 95% CI[0.22-0.90] iu ml-1 for Amax and AUC(0, 24h) respectively). After adjustment for in vitro anti-Xa activity, the statistical difference between the two LMWHs persisted for the AUC(0, 24h) but not for the Amax of plasma anti-Xa activity. The tmax and the MRT values for plasma anti-Xa activity did not significantly differ between the two drugs. The t1/2 for reviparin did not significantly differ from that of enoxaparin (2.7 +/- 0.7 h vs 3.5 +/- 0.9 h respectively, NS). The Amax of the plasma anti-thrombin activity after reviparin administration was also slightly but significantly lower than that observed after enoxaparin administration, (difference between treatments of 0.018 95% CI[0.01-0.025] iu ml-1) whereas the AUC(0, 24h) of anti-thrombin activity vs time was not. A slight but significant increase of the activated partial thromboplastin time of a similar magnitude was observed after both reviparin and enoxaparin injections. 4. The calculated surface under the thrombin generation curve vs time (or thrombin potential) at peak was significantly higher after reviparin than after enoxaparin (367 +/- 53 UA vs 305 +/- 48 UA respectively, P < 0.05). Four hours after injection, thrombin potential was significantly correlated to plasma anti-Xa activity after reviparin but not after enoxaparin injection (r = 0.65, n = 10, P = 0.05 and r = -0.38, n = 10, P = 0.25 respectively). 5. After a single-dose injection in healthy subjects, two LMWHs with comparable in vitro activities differed slightly kinetically. Such minor differences are probably of little importance in the prevention of post-operative deep vein thrombosis, since these two LMWHs were previously shown to be comparable in this setting.     

The interaction of paracetamol with frusemide.

Following the administration of paracetamol (1 g 4 times per day) or placebo to 10 healthy female volunteers for 2 days, the pharmacological effects of intravenous frusemide (20 mg) were observed after a final dose of either paracetamol or placebo. Paracetamol pre-treatment had no effect on frusemide-induced diuresis or natriuresis. There was a significant reduction in the basal output of prostaglandin E2 (PGE2) with paracetamol pre-treatment (18.4 +/- 15.4 vs 7.6 +/- 5.0 ng h-1, P < 0.05; 95% confidence interval of the difference 0.2 to 21.8). Frusemide induced a transient increase in the urinary excretion rate of PGE2 and although this effect was reduced by paracetamol (46.6 +/- 50.9 vs 23.2 +/- 13.8) the differences in the change of excretion rate from baseline were not statistically significant (95% confidence interval of the difference -17.8 to 15.7). The basal level of 6-keto prostaglandin F1 alpha (PGF1 alpha) was less with paracetamol pre-treatment (61.7 +/- 41.1 vs 38.7 +/- 26.1 ng h-1, NS; 95% confidence interval of the difference -16.6 to 62.6) and the cumulative urinary output of PGF1 alpha in the 6 h after frusemide administration was significantly reduced (305.9 +/- 179.4 vs 181.8 +/- 100.2 ng h-1, P < 0.05; 95% confidence interval of the difference 32.2 to 216). The frusemide-induced rise in plasma renin activity was significantly less with paracetamol than placebo at 60 min (4.3 +/- 2.9 vs 2.7 +/- 1.9 ng ml-1 h-1, P < 0.01; 95% confidence interval of the difference 0.4 to 2.7).     

Variability in the stereoselective disposition of ibuprofen in patients with rheumatoid arthritis.

1. Patients suffering from rheumatoid arthritis received oral doses of 600 mg racemic ibuprofen (n = 25; RAC) or 400 mg (S)-ibuprofen (n = 25; S-IBU) in a double-blind, randomized parallel-group study. 2. The pharmacokinetic parameters of (S)-ibuprofen were not statistically different between treatments (P > 0.05). Comparing (S)- and (R)-ibuprofen within the group receiving the racemate significantly higher Cmax (20.3 +/- 5.3 vs 17.7 +/- 4.4 micrograms ml-1; P < 0.02; 95% confidence interval for differences (CI): 0.5-4.6), AUC (86.2 +/- 23.5 vs 67.6 +/- 26.6 micrograms ml-1 h; P < 0.001; CI: 9.5-27.6), mean residence time (4.5 +/- 1.1 vs 4.1 +/- 1.2 h; P < 0.01; CI: 0.1-0.6) and renal clearance (0.8 +/- 0.6 vs 0.0 +/- 0.0 ml min-1; P < 0.001; CI: 0.5-1.0) values were observed for the (S)-enantiomer. 3. No difference was found (P > 0.05) between treatments in the percentage of the dose recovered in the urine as (R)- or (S)-ibuprofen plus metabolites (S-IBU: 80.2 +/- 8.47 vs RAC: 74.1 +/- 14.0%). 4. Interindividual variation in the pharmacokinetics of (S)-ibuprofen following administration of the racemate was similar to that following the administration of the single isomer suggesting that chiral inversion is not a major factor contributing to variability in the disposition of this drug.     

The effect of combined therapy on the pharmacokinetics and pharmacodynamics of verapamil and propranolol in patients with angina pectoris.

1. The pharmacokinetics and pharmacodynamics of oral verapamil and propranolol were studied in patients with stable angina pectoris during chronic mono- and dual therapy. 2. The peak plasma concentrations (Cmax) and areas under the plasma concentration-time curves (AUC) of verapamil were similar during combined treatment with propranolol (mean +/- s.d.: Cmax = 491 +/- 397 ng ml-1; AUC = 2075 +/- 1524 ng ml-1 h) or atenolol (mean +/- s.d.: Cmax = 372 +/- 320 ng ml-1; AUC = 1985 +/- 1660 ng ml-1 h). 3. No differences in Cmax and AUC were observed during verapamil monotherapy (mean +/- s.d.: Cmax = 287 +/- 105 ng ml-1; AUC = 1375 +/- 455 ng ml-1 h) vs combined treatment with propranolol (mean +/- s.d.: Cmax = 312 +/- 55 ng ml-1; AUC = 1566 +/- 486 ng ml-1 h). 4. Treatment with verapamil increased the Cmax (mean +/- s.d.: 227 +/- 117 vs 116 +/- 62 ng ml-1, P less than 0.05) and AUC (1389 +/- 617 vs 837 +/- 316 ng ml-1 h, P = 0.0625) of propranolol in all subjects. 5. Transient atrioventricular dissociation occurred in two patients 2 h after dosing with verapamil and propranolol or atenolol. 6. Close observation of patients is essential when beta-adrenoceptor antagonists and verapamil are used together.     

Effects of itraconazole and diltiazem on the pharmacokinetics of fexofenadine, a substrate of P-glycoprotein

AIMS: Fexofenadine is a substrate of several drug transporters including P-glycoprotein. Our objective was to evaluate the possible effects of two P-glycoprotein inhibitors, itraconazole and diltiazem, on the pharmacokinetics of fexofenadine, a putative probe of P-glycoprotein activity in vivo, and compare the inhibitory effect between the two in healthy volunteers. METHODS: In a randomized three-phase crossover study, eight healthy volunteers were given oral doses of 100 mg itraconazole twice daily, 100 mg diltiazem twice daily or a placebo capsule twice daily (control) for 5 days. On the morning of day 5 each subject was given 120 mg fexofenadine, and plasma concentrations and urinary excretion of fexofenadine were measured up to 48 h after dosing. RESULTS: Itraconazole pretreatment significantly increased mean (+/-SD) peak plasma concentration (Cmax) of fexofenadine from 699 (+/-366) ng ml-1 to 1346 (+/-561) ng ml-1 (95% CI of differences 253, 1040; P<0.005) and the area under the plasma concentration-time curve [AUC0,infinity] from 4133 (+/-1776) ng ml-1 h to 11287 (+/-4552) ng ml-1 h (95% CI 3731, 10575; P<0.0001). Elimination half-life and renal clearance in the itraconazole phase were not altered significantly compared with those in the control phase. In contrast, diltiazem pretreatment did not affect Cmax (704+/-316 ng ml-1, 95% CI -145, 155), AUC0, infinity (4433+/-1565 ng ml-1 h, 95% CI -1353, 754), or other pharmacokinetic parameters of fexofenadine. CONCLUSIONS: Although some drug transporters other than P-glycoprotein are thought to play an important role in fexofenadine pharmacokinetics, itraconazole pretreatment increased fexofenadine exposure, probably due to the reduced first-pass effect by inhibiting the P-glycoprotein activity. As diltiazem pretreatment did not alter fexofenadine pharmacokinetics, therapeutic doses of diltiazem are unlikely to affect the P-glycoprotein activity in vivo.     

Use of pseudoracemic nitrendipine to elucidate the metabolic steps responsible for stereoselective disposition of nitrendipine enantiomers.

1. The pharmacokinetics, protein binding, bioavailability and metabolism of (+)-R- and (-)-S-nitrendipine were studied in six healthy subjects following random oral administration of 20 mg (+)-R-, 20 mg (-)-S- and 20 mg R,S-nitrendipine (pseudoracemic mixture of 10 mg [13C4)-(+)-R- and 10 mg (-)-S-enantiomer). 2. After administration of the enantiomers pronounced differences in AUC (R: 29.9 +/- 20.1; S: 123.8 +/- 63.7 ng ml-1 h; P less than 0.05), bioavailability (R: 10.7 +/- 7.4%; S: 44.6 +/- 23.1%; P less than 0.05) and Cmax (R: 14.4 +/- 7.7; S: 72.5 +/- 40.5 ng ml-1; P less than 0.05) were observed between R- and S-nitrendipine. When racemic nitrendipine was given bioavailability and dose normalized AUC and Cmax values of the S-enantiomer were not different from the values after S-nitrendipine-administration. In contrast, bioavailability (R: 10.7% R,S: 22.1%) and dose normalized AUC (R: 15.0; R,S: 29.5 ng ml-1 h and Cmax (R: 7.2; R,S: 16.8 ng ml-1) of R-nitrendipine were doubled following R,S- as compared with R-nitrendipine administration. t1/2 (R: 9.8; S: 9.1 h) and tmax were not different between the enantiomers nor were the values different after administration of the enantiomers or racemate. The fraction unbound in serum of R-nitrendipine was 0.0098 +/- 0.0032 (s.d.) and that of S-nitrendipine was 0.0083 +/- 0.0015 (s.d.). 3. The AUC values of the major pyridine metabolite M1 were similar after administration of R- and S-nitrendipine (S: 114.7 +/- 48.5; R: 71.7 +/- 29.9 ng ml-1 h).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of ABCB1 (MDR1) haplotypes derived from G2677T/C3435T on the pharmacokinetics of amlodipine in healthy subjects

AIM: We aimed to investigate the effect of the ABCB1 gene on the pharmacokinetics of amlodipine. METHODS: Based on polymorphisms of the ABCB1 gene at positions 2677 and 3435, 26 healthy male participants were divided into three groups: subjects with 2677GG/3435CC (n = 9), 2677GT/3435CT (n = 9) and 2677TT/3435TT (n = 8). After a single-dose administration of 5 mg amlodipine, plasma concentrations of amlodipine were measured and its pharmacokinetic characteristics were compared according to ABCB1 genotype. RESULTS: The area under the plasma concentration-time curve was significantly lower in subjects with 2677TT/3435TT (140.8 +/- 35.6 ng h(-1) ml(-1)) and 2677GT/3435CT (149.8 +/- 40.1 ng h(-1) ml(-1)) than in those with 2677GG/3435CC (208.6 +/- 39.2 ng h(-1) ml(-1)) [95% confidence interval (CI) on the difference, 2677GG/3435CC vs. 2677GT/3435CT 12.0, 105.6, P < 0.01; 2677GG/3435CC vs. 2677TT/3435TT 19.6, 116.0, P < 0.01; 2677GT/3435CT vs. 2677TT/3435TT - 39.2, 57.2, P > 0.05]. The peak plasma concentrations were highest in subjects with 2677GG/3435CC (3.8 +/- 0.5 ng ml(-1)), lower in subjects with 2677GT/3435CT (3.2 +/- 0.5 ng ml(-1)) and 2677TT/3435TT (2.7 +/- 0.5 ng ml(-1)) in rank and showed a significant difference between those with 2677GG/3435CC and with 2677TT/3435TT (95% CI on the difference 0.4, 2.0, P < 0.01). However, the oral clearance was higher in subjects with 2677TT/3435TT (37.7 +/- 10.2 l h(-1)) than in those with 2677GT/3435CT (35.7 +/- 9.9 l h(-1)) and with 2677GG/3435CC (24.8 +/- 5.4 l h(-1)) and exhibited a significant difference between ABCB1 genotype groups (95% CI on the difference, 2677GG/3435CC vs. 2677GT/3435CT - 21.5, - 0.3, P < 0.05; 2677GG/3435CC vs. 2677TT/3435TT - 23.8, - 2.0, P < 0.05). CONCLUSION: Amlodipine pharmacokinetics was affected by the genetic polymorphisms of the ABCB1 gene in humans. These findings may provide a plausible explanation for interindividual variation in the disposition of amlodipine, although our study could not explain the exact mechanism(s) by which the polymorphic ABCB1 gene paradoxically reduces the plasma levels of amlodipine. Further evaluation is thus warranted.     

Pharmacokinetic and pharmacodynamic studies with a new controlled-release formulation of propranolol in normal volunteers: a comparison with other commercially available formulations

The kinetics and dynamics (inhibition of exercise tachycardia) of two controlled-release preparations of propranolol (Elanolol and Inderal LA) were examined in six normal volunteers. Conventional propranolol (Inderal) was also studied for comparison purposes. As compared to conventional propranolol (120 mg), single doses of Elanol (120 mg) and Inderal LA (160 mg) produced a smoother serum level profile, with lower and delayed peak times. Dose-corrected AUC0-24 values were greater after Elanol than after Inderal LA (651 +/- 147 vs 402 +/- 159 ng ml-1 h, means +/- s.e. mean, P greater than 0.05). The profile of inhibition of exercise tachycardia mirrored closely that of the serum levels. At steady state, all regimens studied (Inderal 40 mg three times daily; Elanol 120 mg once daily; Inderal LA 160 mg once daily) ensured relatively sustained serum levels and a stable degree of pharmacological effect. Dose-corrected AUC0-24 values were 797 +/- 148 ng ml-1 h after Inderal, 908 +/- 113 ng ml-1 h after Elanol and 602 +/- 122 ng ml-1 after Inderal LA. The bioavailability of Inderal LA was significantly lower than that of the other preparations. These results demonstrate that long-acting formulations of propranolol can be developed which are not necessarily associated with reduced bioavailability secondary to enhanced first-pass metabolism.     

Grapefruit juice-felodipine interaction: reproducibility and characterization with the extended release drug formulation.

1. Felodipine 10 mg extended release was administered with 250 ml regular-strength grapefruit juice or water in a randomized crossover manner followed by a second grapefruit juice treatment in 12 healthy men. The pharmacokinetics of felodipine and primary oxidative metabolite, dehydrofelodipine, were evaluated. 2. Initial grapefruit juice treatment increased felodipine AUC (mean +/- s.d.; 56.6 +/- 21.9 vs 28.1 +/- 11.5 ng ml-1 h; P < 0.001) and Cmax (8.1 +/- 2.5 vs 3.3 +/- 1.2 ng ml-1; P < 0.001) compared with water. Felodipine tmax (median; 2.8 vs 3.0 h) and t1/2 (7.3 +/- 3.7 vs 6.9 +/- 3.6 h) were not altered. 3. Readministration of felodipine with grapefruit juice produced mean felodipine AUC (61.5 +/- 32.2 ng ml-1 h) and Cmax (8.4 +/- 4.8 ng ml-1) which were similar to the initial grapefruit juice treatment 1-3 weeks previously. Felodipine AUC (r = 0.73, P < 0.01) and Cmax (r = 0.69, P < 0.02) correlated between grapefruit juice treatments among individuals. 4. The % increase in felodipine AUC with the initial grapefruit juice treatment compared with water correlated with the % increase in felodipine Cmax among individuals (r = 0.80, P < 0.01). Dehydrofelodipine AUC (74.7 +/- 28.7 vs 48.5 +/- 16.3 ng ml-1 h; P < 0.01) and Cmax (12.1 +/- 2.9 vs 7.9 +/- 2.6 ng ml-1; P < 0.01) were augmented with grapefruit juice compared with water.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of sex on the pharmacokinetic and pharmacodynamic properties of quinidine

AIMS: To investigate the source of the apparent increased susceptibility of women to develop QT interval prolongation and torsade de pointes after the administration of drugs that delay cardiac repolarization. METHODS: Plasma quinidine concentrations and electrocardiographic changes (QRS and QT intervals) were measured over 24 h following the administration of single oral doses of the QT prolonging drug quinidine (3 mg kg(-1)) and compared between 27 male and 21 female healthy volunteers. RESULTS: There were no significant differences between males and females in plasma quinidine concentrations or in calculated pharmacokinetic variables. Maximum quinidine concentrations in males and females were 997 +/- 56 and 871 +/- 57 ng ml(-1), respectively (mean difference (-125, 95% confidence intervals (CI) -239, 11 ng ml(-1), P = NS). Quinidine lengthened actual (QTa) and corrected (QTc) QT intervals and the QRS interval to a greater extent in females than males (P < 0.001 for each), but there were no significant sex differences detected in the effects of quinidine on the heart rate corrected JT interval. Maximum prolongation of QTc interval was observed 2 h after quinidine and was significantly greater in women (33 +/- 16 vs 24 +/- 17 ms, mean difference 9 +/- 20 ms, 95% CI 3, 15, P = 0.037). At this time mean differences (95% CI) were 1.0 min(-1) (-2.5, 4.4, P = NS) for heart rate, 5.5 ms (3.5, 7.6, P = 0.05) for the QRS and 3.4 ms (-2.5, 9.3, P = NS) for the JTc intervals. CONCLUSIONS: Quinidine-induced increases in QTc were larger in females, but no sex differences in quinidine pharmacokinetics were found. The disparity in prolongation of cardiac repolarization is thus due to a pharmacodynamic difference which appears more complex than simply an increase in repolarization delay in females.     

Metabolic disposition of proguanil in extensive and poor metabolisers of S-mephenytoin 4'-hydroxylation recruited from an Indonesian population.

1. The metabolism of proguanil (PG) was studied by measuring PG, cycloguanil (CG) and 4-chlorophenylbiguanide (CPB) in plasma and urine samples after an oral 200 mg dose of PG hydrochloride administered to 14 extensive (EMs) and 10 poor hydroxylators (PMs) of S-mephenytoin of Indonesian origin. 2. The mean ( +/- s.d.) values of the elimination half-life (t 1/2) and AUC of PG were significantly (P < 0.01) greater in the PM than in the EM group (20.6 +/- 3.1 vs 14.6 +/- 3.5 (95% confidence intervals of difference 3.1 to 8.9) h; and 5.43 +/- 1.89 vs 3.68 +/- 0.83 (0.58 to 2.91) micrograms ml-1 h). 3. Plasma concentrations of CG, an active metabolite, could not be detected in all PMs, and those of CPB were sufficiently high to determine a time-course in only four PMs. Mean AUC(0,24 h) values of CPB were significantly (P < 0.05) lower in the PM (n = 4) than in the EM group (n = 14) (0.47 +/- 0.13 vs 0.88 +/- 0.50 (-0.14 to 0.96) micrograms ml-1 h). 4. Log10 percentage urinary recovery of 4'-hydroxymephenytoin correlated significantly (P < 0.05) with the t 1/2 (rs = -0.661) and AUC (rs = -0.652) of PG. 5. PG, CG and CPB were detectable in urine at 12 h in all subjects. Log10 percentage urinary recovery of 4'-hydroxymephenytoin correlated significantly (P < 0.01) with urinary PG/CG (rs = -0.876), PG/CPB (rs = -0.833) and PG/(CG + CPB) (rs = -0.831) metabolic ratios.(ABSTRACT TRUNCATED AT 250 WORDS)     

C-peptide has no effect on forearm blood flow during local hyperinsulinaemia in healthy humans

BACKGROUND: C-peptide increases forearm blood flow (FBF) in patients with Type 1 diabetes, probably by interaction with insulin, but not in healthy subjects. It is unclear if the vasodilating effect is sealed at normal fasting insulin concentrations. METHODS: The effects of C-peptide alone and during local hyperinsulinaemia were studied in healthy young men. Subjects received intra-arterial insulin at 6 pmol min-1 (low dose) or placebo for 60 min with subsequent coinfusion of C-peptide at increasing doses of 2-60 pmol min-1 in a double-blind crossover study (n = 8). In control experiments insulin at 30 pmol min-1 (high dose) was coinfused with C-peptide (n = 3). FBF was measured by strain-gauge plethysmography. RESULTS: Placebo had no effect on FBF (mean percentage change from baseline at 50 min -3.1%, 95% confidence interval [CI]-14.9, + 8.7). Insulin infusion slightly enhanced FBF by + 10.2% (95% CI -6.8, + 27.2; low dose) and + 17.6% (95% CI -38.8, + 74.0; high dose), respectively. The mean individual difference of the change in FBF between low-dose insulin and placebo was + 13.3% (95% CI -6.0, + 32.7; P = NS). Infusion of C-peptide increased local C-peptide concentrations from 1.8 +/- 0.1 ng ml-1 to 6.1 +/- 2.8 ng ml-1, but had no effect on FBF during placebo or hyperinsulinaemia (mean difference vs low dose insulin -16.0%, 95% CI -38.9, + 6.9). CONCLUSION: The vasodilating effect of C-peptide seen in Type 1 diabetes is not detectable during fasting or hyperinsulinaemia in the forearm vasculature of healthy subjects. This suggests saturation of its vasodilating potency at insulin concentrations within the normal or in the supraphysiological range.     

MDR1 gene polymorphisms and disposition of the P-glycoprotein substrate fexofenadine

AIMS: The C3435T polymorphism in the human MDR1 gene is associated with lower intestinal P-glycoprotein expression, reduced protein function in peripheral blood cells and higher plasma concentrations of the P-glycoprotein substrate digoxin. Using fexofenadine, a known P-glycoprotein substrate, the hypothesis was tested whether this polymorphism also affects the disposition of other drugs in humans. METHODS: Ten Caucasian subjects homozygous for the wild-type allele at position 3435 (CC) and 10 individuals homozygous for T at position 3435 participated in this study. A single oral dose of 180 mg fexofenadine HCl was administered. Plasma and urine concentrations of fexofenadine were measured up to 72 h using a sensitive LC/MS method. In addition, P-glycoprotein function was assessed using efflux of the P-glycoprotein substrate rhodamine 123 from CD56+ cells. Results Fexofenadine plasma concentrations varied considerably among the study population. However, fexofenadine disposition was not significantly different between the CC and TT groups (e.g. AUC(0,infinity) CC vs TT: 3567.1+/-1535.5 vs 3910.1+/-1894.8 ng ml-1 h, NS; 95% CI on the difference -1364.9, 2050.9). In contrast, P-glycoprotein function was significantly decreased in CD56+ cells of the TT compared with the CC group (rhodamine fluorescence CC vs TT: 45.6+/-7.2% vs 61.1+/-12.3%, P<0.05; 95% CI on the difference 5.6, 25.5). Conclusions In spite of MDR1 genotype-dependent differences in P-glycoprotein function in peripheral blood cells, there was no association of the C3435T polymorphism with the disposition of the P-glycoprotein substrate fexofenadine in this German Caucasian study population. These data indicate that other mechanisms including uptake transporter function are likely to play a role in fexofenadine disposition.     

Multiple dose comparison of a whole 240 mg verapamil sustained-release tablet with two half tablets

Twelve healthy male volunteers were studied in a balanced crossover comparison of an intact 240 mg verapamil sustained-release tablet (Securon SR, Isoptin Forte Retard) given once daily for 7 days, and the same dose given as two half tablets. One subject was withdrawn because of asymptomatic second degree heart block on day 3 of verapamil treatment. The mean Cmax after dosing with whole tablets, 143 (95 per cent confidence limits 91.6-223) ng ml-1 was lower than after dosing with half tablets, 160 (107-241) ng ml-1, but this was not significant (p = 0.49). The mean steady-state Cmin values after whole and half tablets were also similar: 22.2 (12.6-39.4) ng ml-1 and 22.0 (16.2-29.9) ng ml-1, respectively (p = 0.96). The mean (+/- S.D.) tmax, AUC0-24 and t 1/2 were not significantly different: whole tablet 3.5 +/- 1.2 h, 1733 +/- 1125 ng.h ml-1 and 10.5 +/- 3.4 h, respectively, and half tablets 3.6 +/- 1.0 h, 1780 +/- 1057 ng.h ml-1 and 9.6 +/- 2.3 h, respectively. The findings for plasma norverapamil were generally similar to those for the parent drug. This investigation indicates that the formulation is sufficiently robust to retain its sustained-release properties when the tablet is halved.     

Single dose disposition of chloroquine in kwashiorkor and normal children--evidence for decreased absorption in kwashiorkor.

The single dose disposition of chloroquine was studied in five children with kwashiorkor and six normal control children after an oral dose of 10 mg kg-1 of chloroquine base. Plasma concentrations of chloroquine and its main metabolite were assayed by high performance liquid chromatography (h.p.l.c.). Chloroquine was detectable for up to 21 days in all the subjects. Chloroquine was detectable in all the subjects within 30 min after giving the drug except in one subject. Peak levels were reached between 0.5 and 8 h in all the subjects (with no significant difference in the tmax between the two groups of children). Peak plasma chloroquine concentrations in the children with kwashiorkor varied from 9 ng ml-1 to 95 ng ml-1 (mean 40 +/- 34 ng ml-1). Peak chloroquine concentrations in the controls varied between 69 ng ml-1 and 330 ng ml-1 (mean 134 +/- 99 ng ml-1). The mean AUC in the kwashiorkor children was significantly lower than the mean AUC in the control children (P less than 0.001). Peak plasma desethylchloroquine concentrations in the children with kwashiorkor varied between 3 and 13 ng ml-1 (mean 6 +/- 9 ng ml-1) while in the controls the concentrations varied between 14 and 170 ng ml-1 (mean 50 +/- 61 ng ml-1). There was no significant difference in the half-life of chloroquine between the kwashiorkor children and the normal control children. The possible influence of a different binding and distribution pattern of chloroquine in kwashiorkor could not be assessed in this study.(ABSTRACT TRUNCATED AT 250 WORDS)     

The disposition of amodiaquine in man after oral administration.

A method is described for the simultaneous determination of amodiaquine (AQ) and desethylamodiaquine (AQm) in plasma, urine, whole blood and packed red cells. After oral administration of AQ (600 mg) to seven healthy subjects, absorption of AQ was rapid, reaching peak concentrations in plasma, whole blood, and packed cells at 0.5 +/- 0.03, 0.5 +/- 0.1 and 0.5 +/- 0.1 h respectively (mean +/- s.e. mean). The apparent terminal half-life of AQ was 5.2 +/- 1.7 h. AQ was detectable for no longer than 8 h. AQ underwent rapid conversion to AQm, which reached peak concentrations in plasma, whole blood and packed cells at 3.4 +/- 0.8, 2.3 +/- 0.5 and 3.6 +/- 1.1 h respectively. AQm was still detectable at the end of the sampling period (96 h) when the plasma concentration was 29 +/- 8 ng ml-1. The area under the plasma concentration vs time curve (AUC(0, infinity] for AQ was 154 +/- 38 ng ml-1 h; the corresponding value for AQm was 8037 +/- 1383 ng ml-1 h. There were no significant differences in the values for AUC of AQ between plasma, whole blood, or packed cells. The whole blood to plasma concentration ratio for AQm was 3.1 +/- 0.2, and the AUC (0.24) for AQm in whole blood (6811 +/- 752 ng ml-1 h) was significantly greater than that in plasma (2304 +/- 371 ng ml-1 h), P less than 0.001. The recovery of AQm from urine collected 0-24 h was 6.8 +/- 0.8 mg (n = 6).(ABSTRACT TRUNCATED AT 250 WORDS)     

Fosinopril/hydrochlorothiazide: single dose and steady-state pharmacokinetics and pharmacodynamics

AIMS: Fosinoprilat, the active product of fosinopril, is eliminated by an hepatic pathway in addition to the renal pathway shared by other angiotensin converting enzyme inhibitors (ACEIs). This study aimed to determine whether impaired renal function affects the pharmacokinetics and pharmacodynamics of a combination of fosinopril and hydrochlorothiazide (HCTZ). METHODS: The study had a parallel-group design comparing patients with renal impairment and body-mass-index-matched normal controls. The study was done in a University clinic in 13 patients with renal impairment (mean creatinine clearance 55.7+/-15.6 ml min-1 1.73 m-2 ) and 13 age-, sex-, and body-mass-index-matched normal controls (mean creatinine clearance 102.4+/-8.9 ml min-1 1.73 m-2 ). All patients and normal controls received fosinopril sodium 20 mg and HCTZ 12.5 mg as a daily oral administration on days 1-5. Non-compartmental pharmacokinetic parameters of fosinoprilat and HCTZ were determined from blood and urine samples obtained over 48 h starting on Day 1 (single dose) and Day 5 (steady state): maximum serum concentration (Cmax ), time to maximum serum concentration (tmax ), area under the serum concentration-time curve during the dosing interval (AUC), cumulative urinary excretion (CUE) and the accumulation index (AI; ratio of AUC-day 5/AUC-day 1). Pharmacodynamic parameters were also measured over 24 h on day 1 and over 48 h on day 5: serum ACE activity and arterial blood pressure. RESULTS: Fosinoprilat pharmacokinetic parameters on day 1 in renally impaired vs normal patients: Cmax=387+/-0.19 vs 324+/-0.25 ng ml-1 (P=0.07); tmax=3.5 vs 3.0 h (P=0.58); AUC=3510+/-0.29 vs 2701+/-0.35 ng ml-1 h (P=0. 072); CUE=5.08+/-2.70 vs 7.40+/-2.56% (P=0.009). Fosinoprilat parameters on day 5: Cmax=517+/-0.40 vs 357+/-0.19 ng ml-1 (P=0. 007); tmax=3.0 vs 3.0 h (P >0.99); AUC=4098+/-0.43 vs 2872+/-0.30 ng ml-1 h (P=0.027); CUE=6.81+/-3.53 vs 8.10+/-2.80% (P=0.068). AI=1. 17+/-0.33 vs 1.06+/-0.23 (P=0.29). In both groups ACE inhibition and blood pressure response were similar over 24 h and slightly greater 48 h after last dosing. CONCLUSIONS: In renally impaired subjects fosinopril and HCTZ can be coadministered without undue increases in fosinoprilat concentrations or any clinically significant pharmacodynamic effects. This is probably due to the dual excretory pathways for fosinoprilat.     

Buspirone pharmacokinetics in patients with cirrhosis.

The pharmacokinetics of a single oral dose of buspirone (20 mg) were determined in 12 patients with cirrhosis and 12 normal subjects. The mean AUC of buspirone was 55 +/- 38 s.d. ng ml-1 h in cirrhotics and 3.5 +/- 2.4 s.d. ng ml-1 h in normals. The time until maximum concentration (tmax) attained was similar in the two groups (0.6 vs 0.7 h), but mean maximum concentration Cmax was higher in patients (18.8 +/- 16.3 s.d. ng ml-1) than in normals (1.2 +/- 0.8 s.d. ng ml-1). Mean elimination half-life of buspirone was greater in cirrhotics, but this difference was marginally significant statistically (cirrhotics, 6.1 +/- 3.5 s.d. h, normals 3.2 +/- 1.5 s.d. h, P = 0.05). Eight of 12 patients and seven of 12 normal subjects had a second peak in the plasma concentrations of buspirone. In patients this occurred at 10.8 +/- 7.4 s.d. h after the dose, and its mean concentration was 3.1 +/- 6.6 ng ml-1. In normal subjects the second peak occurred at 4.3 +/- 2.1 h after the dose and its mean concentration was 0.5 +/- 0.3 ng ml-1. On the kinetic evidence buspirone should be used with caution in liver disease.