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 One subject was withdrawn because of asymptomatic second degree heart block on day 3 of verapamil treatment.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.     

The relative bioavailability of diclofenac with respect to time of administration.

The pharmacokinetics of diclofenac after a single oral dose (50 mg) were studied in 10 healthy adults on two occasions separated by 2 weeks, once in the morning (dose administered at 07.00 h) and once in the evening (dose at 19.00 h). Peak serum drug concentrations as well as the area under the drug concentration-time curve were significantly less during the night compared with the day (Cmax: 1886 +/- s.d 901 vs 2791 +/- 1565 ng ml-1 and AUC: 2807 +/- 1376 vs 3681 +/- 1986 ng ml-1 h). However, the time to reach peak concentration (tmax) and the half-life of diclofenac (t1/2) were not significantly different on the two occasions. We suggest that the extent of diclofenac absorption is slightly lower following administration in the evening compared with administration in the morning.     

Pharmacokinetic and pharmacodynamic profile following oral administration of the phosphodiesterase (PDE)4 inhibitor V11294A in healthy volunteers

AIMS: To assess the pharmacokinetic and pharmacodynamic profile of the novel PDE4 inhibitor V11294A (3-(3-cyclopentyloxy-4-methoxybenzyl)-6-ethylamino-8-isopropyl-3H purine hydrochloride) in healthy male volunteers. METHODS: This was a double-blind, single dose, randomized crossover study in eight healthy volunteers who received a single oral, fasting dose of V11294A (300 mg) or placebo. Blood samples were taken before and 0.5, 1, 2, 2.5, 3, 4, 6, 9, 12, 18 and 24 h after oral dosing for determination of plasma concentrations of V11294A. Blood samples were also taken before and 3 and 24 h after dosing for the assessment of the effect of V11294A on mononuclear cell proliferation and tumour necrosis factor (TNF) release in whole blood. RESULTS: Following a single oral dose of 300 mg V11294A, plasma concentrations of V11294A and its active metabolite V10332 reached Cmax (ng ml-1; mean +/- s.d.; 1398 +/- 298, 1000 +/- 400, respectively) after 2.63 +/- 0.79 and 5.9 +/- 2.3 h, respectively. For V11294A and V10332, t1/2 were 9.7 +/- 3.9 and 9.5 +/- 1.7 h, and AUC(0, infinity ) were 18100 +/- 6100 and 18600 +/- 8500 ng ml-1 h, respectively. At 3 h dosing, plasma concentrations of V11294A and V10332 (3-(3-cyclopentyloxy-4-methoxy-benzyl)-8-isopropyl-3H-purin-6-ylamine) were 1300 +/- 330 and 860 +/- 300 ng ml-1, 7 and 3 times their in vitro IC50s for inhibition of TNF release and proliferation, respectively. Treatment with V11294A resulted in a significant reduction of lipopolysaccharide (LPS)-induced TNF release at 3 h (P < 0.001) and at 24 h (P < 0.05) post ingestion. The amount of TNF released (pmol ml-1) in response to a submaximal concentration of LPS (4 ng ml-1) was not significantly altered following placebo treatment (before 681 +/- 68 vs 3 h postdose 773 +/- 109, P = 0.27). In contrast, there was a significant reduction in the amount of TNF released following treatment with V11294A (before 778 +/- 87 vs 3 h postdose 566 +/- 72, P = 0.02). Phytohaemagluttinin (PHA) stimulated the incorporation of [3H]-thymidine in whole blood prior to drug administration. V11294A inhibited the PHA-induced proliferation at 3 h (P < 0.05). No adverse reactions were noted following single oral administration of V11294A. CONCLUSIONS: A single oral 300 mg dose of V11294A administered to healthy volunteers results in plasma concentrations adequate to inhibit activation of inflammatory cells ex vivo, which persists for at least 24 h without any adverse reactions.     

Pharmacodynamic effects and pharmacokinetics of a new HMG-CoA reductase inhibitor,rosuvastatin, after morning or evening administration in healthy volunteers

AIMS: To compare the lipid-regulating effects and steady-state pharmacokinetics of rosuvastatin, a new synthetic hydroxy methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, following repeated morning and evening administration in volunteers with fasting serum low-density lipoprotein cholesterol (LDL-C) concentrations < 4.14 mmol l-1. METHODS: In this open-label two-way crossover trial 24 healthy adult volunteers were randomized to receive rosuvastatin 10 mg orally each morning (07.00 h) or evening (18.00 h) for 14 days. After a 4 week washout period, volunteers received the alternative regimen for 14 days. Rosuvastatin was administered in the absence of food. RESULTS: Reductions from baseline in serum concentrations of LDL-C (-41.3%[morning]vs-44.2%[evening]), total cholesterol (-30.9%vs-31.8%), triglycerides (-17.1%vs-22.7%), and apolipoprotein B (-32.4%vs-35.3%) were similar following morning and evening administration. AUC(0,24 h) for plasma mevalonic acid (MVA), an in vivo marker of HMG-CoA reductase activity, decreased by -29.9% (morning) vs-32.6% (evening). Urinary excretion of MVA declined by -33.6% (morning) vs-29.2% (evening). The steady-state pharmacokinetics of rosuvastatin were very similar following the morning and evening dosing regimens. The Cmax values were 4.58 vs 4.54 ng ml-1, and AUC(0,24 h) values were 40.1 vs 42.7 ng ml-1 h, following morning and evening administration, respectively. There were no serious adverse events during the trial, and rosuvastatin was well tolerated after morning and evening administration. CONCLUSIONS: The pharmacodynamic effects and pharmacokinetics of rosuvastatin are not dependent on time of dosing. Morning or evening administration is equally effective in lowering LDL-C.     

The metabolism of [14C]N-ethoxycarbonyl-3-morpholinosydnonimine (molsidomine) in man

[14C]-N-Ethoxycarbonyl-3-morpholinosydnonimine (molsidomine, Corvaton) was administered orally at a dose of 2 mg per subject to eight healthy male volunteers. Maximal plasma concentrations of total radioactivity of 32.4 +/- 6.4 ng equiv./ml (mean +/- S.D.) were detected compared with maximum plasma concentrations of 14.1 +/- 5.9 ng/ml (mean +/- S.D.) of molsidomine. In both cases these were attained at 0.5 h after dosing. From the peak, concentrations of parent drug fell rapidly with a half-life of 1.25 +/- 0.38 h (mean +/- S.D.). In contrast, total radioactivity declined more slowly with a terminal half-life of 138 +/- 42.7 h (mean +/- S.D.). The bulk of the radiolabel was rapidly excreted as metabolites in the urine, with over 85% of the dose recovered in the first 24 h. The main urinary radiolabelled metabolites appeared, from chromatographic evidence, to be similar to those previously identified in animals, namely N-morpholinosydnonimine, N-cyanomethylamino-N-(2'-hydroxyethyl)glycine and (N-cyanomethylenamino-2-aminoethoxy)-acetic acid.     

Pharmacokinetics of dibenzylamine administered in a sustained drug delivery system with cefazolin

The pharmacokinetics of dibenzylamine administered in a sustained drug delivery system with cefazolin was studied after i.m. administration of a dose of 1250 mg to healthy volunteers. The serum and urine levels of dibenzylamine were determined by a GLC technique using a specific nitrogen-phosphorus detector. Characterization of the kinetic parameters was performed by applying compartmental and non-compartmental analysis. Dibenzylamine was found to reach concentrations close to 300 ng ml-1 approximately 5 h after administration. The elimination constant had a value of 0.832 +/- 0.821 h-1 (mean +/- S.D.), which is higher than the release constant of the derivative (0.109 +/- 0.072 h-1) (mean +/- S.D.). These results show that release of dibenzylamine may be considered the limiting kinetic process, which governs the elimination of the product from the organism. Only a small amount of dibenzylamine is excreted in urine unchanged 3.43 +/- 3.28 per cent (mean +/- S.D.). Using the pharmacokinetic parameters calculated for dibenzylamine, a prediction has been made of the concentrations reached in a multiple dosage regimen after administration of a dose of 1250 mg every 24 h. The accumulation factor was 1.09.     

The pharmacokinetics of subcutaneously injected Bimosiamose disodium in healthy male volunteers

Bimosiamose is a novel synthetic pan-selectin antagonist developed for the treatment of acute and chronic inflammatory disorders. Therefore the pharmacokinetics of Bimosiamose disodium were studied in healthy male volunteers after single and multiple subcutaneous injections. A randomized, double-blind, placebo-controlled dose escalation trial was carried out. The subjects received subcutaneous injections of placebo or 100, 200 or 300 mg Bimosiamose disodium into the abdomen. Plasma and urine concentrations of Bimosiamose were determined. The maximum plasma concentration was 2.17+/-0.70 microg/ml and the AUC(0-infinity) 11.1+/-2.9 h microg/ml after the highest dose on day 1 (mean+/-SD). For the apparent clearance CL/f 28.7+/-7.3 l/h and the terminal half life t(1/2) 3.7+/-0.6 h were calculated. The mean residence time MRT(infinity) of 5.5 to 6.3 h for s.c. injection exceeded that after i.v. infusion due to an extended absorption time. For multiple dosing, constant pre-dose concentrations of about 20 ng/ml may be reached after two subsequent doses of 200 or 300 mg Bimosiamose disodium once daily. Almost 15% of the administered drug was excreted unchanged in urine. Moreover, Bimosiamose was well tolerated.     

Pharmacokinetics of oxatomide given percutaneously to healthy volunteers.

The percutaneous absorption of oxatomide gel at 5 per cent concentration was studied after single and repeated administration (85 mg b.i.d.) in six male and six female healthy volunteers, aged 25.7 +/- 0.8 years (mean +/- SEM) weighing 64.4 +/- 4.5 kg and the results compared with those obtained following a single oral dose (30 mg). The measurement of oxatomide was by means of a new sensitive and specific HPLC assay with limits of detection of 0.2 ng ml-1 in plasma and 1.0 ng ml-1 in urine. Poor percutaneous absorption was confirmed by the peak plasma concentrations which were 5.03 +/- 0.79 ng ml-1 following application of the gel for 7 days and 10.08 +/- 1.29 ng ml-1 following oral administration; the corresponding amounts of unchanged oxatomide recovered from 24 h urine collections were 1.42 +/- 0.39 micrograms and 3.93 +/- 0.92 micrograms.     

Comparative pharmacokinetics of ketoprofen derived from single oral doses of ketoprofen capsules or a novel sustained-release pellet formulation

Nine healthy male volunteers took part in a crossover study to compare the pharmacokinetics of ketoprofen after administration of a single oral dose (200 mg) of ketoprofen as 'Orudis' capsules or encapsulated sustained-release pellets, 'Oruvail'. The mean +/- standard deviation values for highest observed plasma ketoprofen concentrations were determined by high performance liquid chromatography to be 23 +/- 11 micrograms ml-1 at 0.82 +/- 0.18 h after dosing with ketoprofen capsules and 3.5 +/- 1.0 micrograms ml-1 at 4.9 +/- 1.0 h after dosing with sustained-release pellets. The apparent ketoprofen elimination half-lives after these treatments were 3.3 +/- 1.2 h and 8.4 +/- 3.4 h, respectively. The systemic availability of ketoprofen was essentially the same after each treatment. Administration of sustained-release pellets (containing 200 mg ketoprofen) once every 24 h is predicted to produce similar average and markedly higher minimum plasma ketoprofen concentrations than are produced by ketoprofen capsules (100 mg) every 12 h, and similar minimum plasma ketoprofen concentrations to those achieved by dosing ketoprofen capsules (50 mg) every 6 h. Once-daily administration of a non-steroidal anti-inflammatory agent has an obvious therapeutic advantage over more frequent dosing. This study suggests that the sustained-release pellet formulation described herein is a suitable formulation for once-daily administration of ketoprofen.     

Pharmacokinetics of temazepam after day-time and night-time oral administration

Summary The pharmacokinetic disposition of temazepam was compared after a day-time and night-time dose in an open randomised crossover study. Twelve healthy male volunteers received a single oral dose of 20 mg temazepam in a soft gelatine capsule at 0900 h or 2200 h. Blood samples were taken immediately before dosing and at selected times over the 36-h period after each dose.The absorption of temazepam was slower after evening administration; the absorption half-life and time to reach maximal plasma concentration being 0.53 h and 1.67 h respectively, compared to 0.38 h and 1.02 h following morning administration. Considering distribution characteristics, evening administration produced a lower peak plasma temazepam concentration (362 ng/ml) compared with a day-time level of 510 ng/ml. Distribution half-life after night-time administration was increased compared with day-time administration (1.76 h vs 1.03 h). A significantly higher percentage of the drug, relative to C_max, remained in the plasma at 8 and 24 h after evening dosing (39.3 and 15.4% compared to 24.7 and 11.2% following day-time administration). In spite of the half-lives of absorption, distribution and elimination all being longer after the evening dose, the overall bioavailability, as measured by the area under the curve (AUC) was comparable after the two times of administration. Similarly the difference in the mean residence time (MRT) of the two doses was within accepted limits.It is concluded that a chronopharmacokinetic effect was seen for temazepam; however it is unlikely to be of any clinical significance.     

Pharmacokinetic profile of a new controlled-release isosorbide-5-mononitrate 60 mg scored tablet (Monoket Multitab).

The influences of food, tablet splitting, and fractional dosing on the pharmacokinetics of a new controlled-release double-scored tablet containing 60 mg isosorbide-5-mononitrate (Monoket Multitab) were investigated in healthy male volunteers. Food interaction was evaluated after single dose administration under fasted conditions and after a standard high-fat breakfast. The effect of tablet splitting was assessed at steady-state, after 5 days of once daily dosing with the tablet taken intact or trisected. The influence of fractional dosing was assessed after 1 and 6 days of daily regimen of 40 mg in the morning (2/3 of a tablet) and 20 mg in the evening (1/3 of a tablet). The pharmacokinetics of isosorbide-5-mononitrate after taking the tablet intact or in three fragments were very similar with a mere 10% increase of maximum plasma concentration (C(max)) for the latter, while the time to peak (T(max)) decreased from 5 to 4 h and areas under the concentration vs. time curves (AUCs) were virtually unchanged. Morning trough concentration reached 53 and 46 ng/ml, respectively. Administration of the intact tablet after a high-fat breakfast increased C(max) by 18% and AUC by 21%, and slightly delayed T(max) from 5 to 6h. During fractional dosing, morning and evening C(max) reached 364 and 315 ng/ml on the first day, and 373 and 300 ng/ml on the 6th day, respectively. The ratio of AUC(0-24 h) on the last day to AUC(infinity) on the first day, was 82.1% (confidence limits 71.7-94.1%) possibly resulting from peripheral volume expansion. The release characteristics of Monoket Multitab are thus moderately influenced by concomitant intake of food and to a very minor extent by tablet breaking. Fractional dosing allows to achieve lower peak and higher morning trough levels, while total exposure is comparable to that during once daily dosing (AUC(0-24 h, s.s.) of 5.55+/-1.78 and 5.71+/-1.08 microg h/ml).     

Plasma concentrations and pharmacokinetics of dihydralazine after single oral doses to human subjects

After single oral doses of 20 mg of a suspension of dihydralazine sulphate to human subjects, the peak of mean plasma concentrations of dihydralazine of 47.0 ng ml-1 +/- 11.0 standard deviation (S.D.) (n = 7) was reached at 1 h. Mean concentrations declined biphasically with apparent half-lives of 0.57 and 4.96 h respectively. Dihydralazine was partly converted to hydralazine. The peak of mean plasma concentrations of the latter drug of 3.9 ng ml-1 +/- 1.7 S.D. (n = 7) occurred at 1-2 h after dosing with dihydralazine sulphate and declined to 1.5 ng ml-1 +/- 1.5 S.D. at 6 h. Of the seven subjects studied, three were classified as fast and four as slow acetylators. Mean clearances appeared to be slightly more rapid in fast acetylators (1.63 l min-1 +/- 0.32 S.D.) when compared to slow acetylators (1.31 l min-1 +/- 0.31 S.D.) but this difference and differences in plasma concentrations and in areas under the plasma drug concentration-time curves were not significant (p > 0.1).     

The pharmacokinetics of mefloquine in man: lack of effect of mefloquine on antipyrine metabolism.

A method is described for the determination of the new antimalarial agent, mefloquine, in plasma and urine. After oral administration of 750 mg mefloquine to six volunteers, absorption, was apparently slow, with plasma mefloquine concentrations at 24 h (559 +/- 181 ng ml-1; mean +/- s.d.) higher than at 6 h (459 +/- 166 ng ml-1). The elimination half-life was 373 +/- 249 h, oral clearance was 5.09 +/- 2.7 1 h-1, and apparent volume of distribution was 35.7 +/- 30.7 l kg-1 (assuming 100% bioavailability). Mefloquine (750 mg) had no significant effect on salivary kinetics of antipyrine or on the metabolic clearance of antipyrine to its three main metabolites, 3-hydroxymethylantipyrine, 4-hydroxyantipyrine and norantipyrine, when antipyrine was administered either 2 h or 2 weeks after dosing with mefloquine.     

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.     

高效液相色谱法测定人血清和尿中盐酸青藤碱浓度及药代动力学研究

用RP-HPLC法,以三唑仑为内标,反相C₁₈为分析柱,乙腈—0.01mol·L^-1磷酸二氢钠—四甲基乙二胺(46∶54∶0.22v/v)为流动相,磷酸调至pH6.9,检测波长263nm,测定血清和尿中盐酸青藤碱浓度,线性范围分别为6～480ng·mL^-1和0.06～3μg·mL^-1,平均回收率75.88%和91.35%,日内日间误差小于5%,最低检测浓度血清4ng·mL^-1,尿40ng·mL^-1。8名健康男性志愿者单次口服盐酸青藤碱片80mg,测定血清及尿浓度,该药符合二室开放模型,体内消除符合一级动力学消除过程,主要药代动力学参数:T_1/2α0.791±0.491h,T_1/2β9.397±2.425h,T_{max 1.040±0.274h,Cmax246.604±71.165ng·mL^-1,AUC 2651.158±1039.050ng·h·mL^-1,CL 0.033±0.01ng·mL^-1。}     

Acute and chronic pharmacokinetics of asymmetrical doses of slow release choline theophyllinate in asthma.

The day and night pharmacokinetics of assymetrical doses of slow release choline theophyllinate (Sabidal SR 270) were compared at day 1 and at day 4 of treatment when steady state had been achieved. Ten patients with chronic asthma were given oral choline theophyllinate 424 mg at 09.00 h and 848 mg at 21.00 h for 4 days. At regular intervals during day 1 and day 4 of treatment theophylline concentrations were measured in plasma and dried blood spots by fluorimmunoassay. Theophylline concentrations measured from dried blood spots were slightly lower than those in plasma, the difference remaining constant at all time points during day 1 and day 4 of treatment. On day 1 the mean peak plasma theophylline concentration was 5.4 +/- 1.0 (+/- s.e. mean) micrograms ml-1 4 h after the morning dose and 11.2 +/- 1.6 micrograms ml-1 4 h after the evening dose which were significantly (P less than 0.01) different. Similarly the areas under the plasma theophylline concentration-time curves at night were significantly (P less than 0.001) greater than those observed during the day. During day 4 mean peak plasma concentrations of theophylline after the morning and larger evening dose were 13.2 +/- 1.3 and 12.1 +/- 1.4 micrograms ml-1 respectively, which were not significantly different. No significant difference was observed between the areas under the plasma theophylline concentration-time curves during the day and at night. However the post-dose time to peak was significantly delayed at night (6 h) compared to the morning (2 h, P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of epanolol after acute and chronic oral dosing in elderly patients with stable angina pectoris.

1. Epanolol is a novel anti-anginal agent which is a beta 1-adrenoceptor partial agonist exhibiting selective beta 1-adrenoceptor antagonist and selective beta 1-adrenoceptor agonist activity. It is mainly metabolised to conjugates prior to excretion in urine and it was of interest to determine if any accumulation occurred in elderly patients. 2. The pharmacokinetics of epanolol have been studied over 72 h after a single oral dose of 200 mg and then over 24 h after 12 consecutive daily oral doses in 13 elderly patients with stable angina pectoris. 3. The peak plasma concentrations (mean +/- s.d.) after the single dose (25.7 +/- 17.0 ng ml-1) were not significantly different (P = 0.35) from those at steady state (32.4 +/- 20.9 ng ml-1). There was wide inter-individual variation on both occasions. The time to peak did not alter significantly during the study with mean values of 1.5 and 1.2 h on acute and chronic dosing respectively. 4. Plasma concentrations declined biphasically with a mean terminal phase half-life of 17 h and 5 fold inter-individual variation. 5. The mean area under the curve to 24 h was not significantly different (P = 0.26) after the single dose (59.0 +/- 29.8 ng ml-1 h) from that at steady state (78.4 +/- 55.0 ng ml-1 h). There was also wide inter-individual variation in these values. 6. In conclusion, the lack of significant accumulation of epanolol indicates that no alteration of dose is necessary when using epanolol in elderly patients with normal renal and hepatic function.     

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.     

Comparative bioavailability of tetracycline and lymecycline

The relative bioavailability of lymecycline and tetracycline hydrochloride was compared in 12 healthy volunteers in a double-blind cross-over study using a high performance liquid chromatographic method for plasma and urine analyses. A statistical significant difference in favour of tetracycline hydrochloride was found concerning the mean AUC and the mean lag time. The relative bioavailability of lymecycline was only 70% compared with tetracycline in multiple dosing (19.13 +/- 5.39 micrograms ml-1 h and 27.22 +/- 6.26 micrograms ml-1 h respectively) and 80% in a single dose (21.88 +/- 4.23 micrograms ml-1 h and 26.91 +/- 6.01 respectively) and the mean lag time of tetracycline was only 60% compared with lymecycline.     

The effect of dosing time on the pharmacokinetics and pharmacodynamics of a 'once-a-day' sustained release theophylline preparation.

1. The pharmacokinetics and the bronchodilating effect of theophylline were studied during 1 week of morning dosing and 1 week of evening dosing in a randomized cross-over design in thirteen patients with reversible airways obstruction, treated with a new 'once-a-day' theophylline capsule formulation. 2. There were no differences between the mean pre-dose trough plasma concentration, maximal plasma concentration, trough-to-peak variation, tmax, area under the plasma drug concentration time-curve after morning or evening dosage. There was only a slightly but significantly higher plasma theophylline concentration between 16 and 20 h after evening dosing. 3. The mean plasma drug concentration time-curves were relatively flat with a mean trough to peak variation of 73.9% after morning dosing and 66.7% after evening dosing. Both sets of mean data were within the 10-20 mg l-1 therapeutic range. 4. The variations in FEV1 and PEFR throughout the 24 h after either morning or evening dosing were similar and followed the normal pattern of diurnal variation. 5. Adverse effects were mild and occurred in three patients without causing discontinuation of the study. 6. The theophylline preparation used appears suitable for once a day administration either in the morning or in the evening.