Single dose pharmacokinetics of proguanil and its metabolites in healthy subjects.

1. Plasma and whole blood concentrations of proguanil and its two major metabolites cycloguanil (CG) and 4-chlorophenylbiguanide (CPB) were measured by a sensitive h.p.l.c. technique in nine healthy adult male volunteers after a single oral dose of proguanil 200 mg. 2. Proguanil was absorbed with a median time to peak plasma concentration of 3 h (range 2-4 h). 3. Peak plasma concentrations of proguanil ranged between 150 and 220 (median 170) ng ml-1 compared with 12 to 69 (median 41) ng ml-1 for the active antimalarial metabolite CG, and 3 to 16 (median 11) ng ml-1 for CPB. Peak (mean +/- s.d.) plasma CG concentrations occurred 5.3 +/- 0.9 h and peak CPB concentrations occurred 6.3 +/- 1.4 h after oral administration of proguanil. 4. Whole blood concentrations of proguanil were approximately five times higher, and whole blood CPB concentrations were four times higher than corresponding plasma values, whereas plasma and whole blood concentrations of CG were similar. 5. A triexponential function was fitted to these data; mean (+/- s.d.) values for the AUC were 3046 +/- 313 ng ml-1 h for proguanil, 679 +/- 372 ng ml-1 h for CG and 257 +/- 155 ng ml-1 h for CPB. 6. Plasma and whole blood concentrations of proguanil and its metabolites declined in parallel with terminal elimination half-lives estimated as 16.1 +/- 2.9 h and 15.7 +/- 2.4 h, respectively. Mean residence times in plasma and whole blood were estimated as 21.2 +/- 4.9 and 19.3 +/- 2.4 h.     

A new approach to evaluate stability of amodiaquine and its metabolite in blood and plasma

A stability study for amodiaquine (AQ) and desethylamodiaquine (AQm) in whole blood and plasma is reported. AQ, AQm and chloroquine (CQ) were simultaneously analysed and the ratios AQ/CQ and AQm/CQ were used to ensure correct interpretation of the stability results. CQ was stable in whole blood and plasma at all tested temperatures enabling it to be a stability marker in stability studies. Simultaneous analysis of compounds, of which at least one is already known to be stable, permits a within sample ratio to be used as a stability indicator. The new approach significantly reduced bias when compared to the traditional approach. AQ and AQm were stable in plasma at -86 degrees C and -20 degrees C for 35 days, at 4 degrees C for 14 days and at 22 degrees C for 1 day. AQ and AQm were stable in blood at -86 degrees C and 4 degrees C for 35 days, at -20 degrees C and 22 degrees C for 7 days and at 37 degrees C for 1 day.     

Tissue distribution and excretion of amodiaquine in the rat

14C-Labelled amodiaquine ([14C]AQ) has been administered to male Wistar rats by oral and intravenous routes (n = 6 for each route of administration). Excretion of total 14C-activity was predominantly in the faeces after both oral and intravenous administration. After oral administration 86 +/- 8.3% (mean +/- s.d.) of the 14C administered had been excreted (77 +/- 9% in the faeces, 7 +/- 1% in the urine and 2 +/- 2% in cage washings) over 72 h. Of the 14C administered, 4 +/- 1% was recovered from the tissues, and this was widely distributed, with the main organs of accumulation being kidney, liver, red bone marrow and spleen. After intravenous administration, 102.6 +/- 9.7% of the 14C had been excreted (90.9 +/- 9.6% in faeces, 10.9 +/- 0.8% in urine and 0.5 +/- 0.2% in cage washings) over 72 h. High-performance liquid chromatographic analysis of urine and faeces samples following oral administration of 14C-AQ (8.6 mg kg-1; base) revealed recoveries of 210 +/- 70 micrograms amodiaquine (AQ) and 123 +/- 32 micrograms desethylamodiaquine (AQm) in the faeces, and 2.4 +/- 0.5 micrograms AQ and 18.5 +/- 4.1 micrograms AQm in the urine. Female Wistar rats (n = 6) each received [14C]AQ orally and were killed at the following times: 0.5, 1, 3, 6, 24 and 48 h. Autoradiographs were prepared from each animal and these revealed significant amounts of radioactivity in the tissues at 48 h. This was accumulated maximally by liver and kidney. Radioactivity was detected in bone marrow at 48 h.(ABSTRACT TRUNCATED AT 250 WORDS)     

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)     

Pharmacokinetics of co-administered didanosine and stavudine in HIV-seropositive male patients.

The pharmacokinetics of single and co-administered didanosine and stavudine were evaluated in 10 HIV-seropositive subjects in an open, within subject design in which each subject received each of three treatments. Single doses of didanosine 100 mg were alternated randomly with single doses of stavudine 40 mg on days 1 and 2. Beginning on day 3, subjects received the same doses of both drugs simultaneously every 12 h for nine doses. Serial blood and urine samples were obtained on single dose days 1 and 2, first simultaneous dose day 3, and last simultaneous dose day 7. The average maximum plasma concentrations of didanosine and stavudine before and after simultaneous administration were 422 +/- 184 (s.d.) ng ml-1 and 603 +/- 160 (s.d.) ng ml-1, and 419 +/- 153 (s.d.) ng ml-1 and 726 +/- 188 (s.d.) ng ml-1, respectively. Didanosine and stavudine AUC values before and after simultaneous administration were 615 +/- 170 (s.d.) ng ml-1 h and 1246 +/- 230 (s.d.) ng ml-1 h, 637 +/- 155 (s.d.) ng ml-1 h and 1326 +/- 267 (s.d.) ng ml-1 h, respectively. No significant changes in maximum plasma concentration, AUC elimination half-life, or renal clearance of didanosine and stavudine were observed when the drugs were administered simultaneously. Co-administration of didanosine 100 mg and stavudine 40 mg is well tolerated and the drugs do not interact pharmacokinetically.     

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.     

Effect of dose size on amodiaquine pharmacokinetics after oral administration

Summary Plasma and urine concentrations of amodiaquine (AQ) and desethylamodiaquine (AQm) have been measured after oral administration of AQ 200, 400 and 600 mg in randomised order to 6 healthy subjects.The relationships between AQ dose size and the areas under the plasma concentration vs time curves for AQ and AQm were linear. Likewise there were linear relationships between AQ dose size and the mass of both AQ and AQm excreted in the urine.These data indicate that after oral administration within this dose range AQ displays first-order pharmacokinetics.     

Divided-dose kinetics of mefloquine in man.

The kinetics of mefloquine was investigated following oral divided-doses in 10 healthy Caucasian volunteers. They received 500 or 750 mg followed by 500 mg 8 h later. Unchanged mefloquine (M) and its carboxylic acid metabolite (MM) were measured in whole blood and plasma for 50 days by h.p.l.c. Maximum blood and plasma M concentrations of 1872 +/- 362 ng ml-1 (mean +/- s.d.) and 1900 +/- 434 ng ml-1, respectively, were found within 6-10 h after the second dose. The terminal plasma elimination half-life was 20.1 +/- 3.7 days (mean +/- s.d.) and the oral clearance was 22.3 +/- 6.7 ml h-1 kg-1 (mean +/- s.d.). Plasma concentrations of MM exceeded those of M by 2-3 fold within 2 days. The whole blood concentration of MM was lower than that in plasma but also exceeded the whole blood concentration of M.     

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。}     

Alinidine pharmacokinetics following acute and chronic dosing.

1 Alinidine (N-allyl clonidine) pharmacokinetics were investigated in healthy volunteers following acute administration of 40 mg orally and intravenously (i.v.) and chronic administration of 40 mg daily and twice daily for 8 days. 2 After acute oral administration the following values were obtained; Cmax -- 166.5 +/- 18.5 ng/ml at 1.8 +/- 0.7 h (mean +/- s.d., n = 5); AUC -- 1122.9 ng ml-1 h; VdSS -- 190.71 and T1/2 -- 4.2 h, and after i.v. administration: AUC -- 1046.7 ng ml-1 h; VdSS -- 190.71 and T1/2 4.2 h. 3 Clonidine was identified in plasma and urine samples following oral and i.v. administration; clonidine Cmax was 0.26 +/- 0.06 ng/ml at 8.4 +/- 2.2 h and 0.5 +/- 0.2 ng/ml at 4.8 +/- 2.5 following oral and i.v. alinidine respectively. Urinary excretion of clonidine represented 0.1% of the administered dose of alinidine. 4 During administration of alinidine 40 mg daily for 8 days, peak and trough plasma levels reached steady state after day 2 (223.1 +/- 123.9 and 9.03 +/- 6.7 ng/ml respectively). During alinidine 40 mg twice daily for 8 days peak and trough plasma levels on day 2 were 356.2 +/- 92.0 and 80.0 +/- 35.8 ng/ml respectively, these levels did not change (P greater than 0.05) between days 2 and 8. Urine elimination of alinidine did not change (P greater than 0.05) between days 5, 6, 7 and 8. 5 Clonidine plasma concentration following alinidine 40 mg daily and twice daily were 0.47 +/- 0.18 and 0.84 +/- 0.21 ng/ml respectively 2 h after administration on day 2 and did not change (P less than 0.05) between days 2-8. 6 It is unlikely that clonidine formed from alinidine contributes to the pharmacological action of alinidine.     

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.     

The influence of diflunisal on the pharmacokinetics of oxazepam.

Single dose pharmacokinetics of oxazepam, 30 mg, have been studied in six healthy male volunteers in the absence of diflunisal and during continuous treatment with diflunisal 500 mg twice daily. During diflunisal treatment, peak plasma concentration of oxazepam significantly decreased from 387 +/- 18 ng ml-1 (mean +/- s.e. mean) to 241 +/- 10 ng ml-1 and total area under the plasma concentration-time curve (AUC) significantly decreased from 5536 +/- 819 ng ml-1 h to 4643 +/- 562 ng ml-1 h. The AUC of oxazepam glucuronide significantly increased from 4771 +/- 227 ng ml-1 h to 8116 +/- 644 ng ml-1 h and its elimination half-life increased from 10.0 +/- 0.6 h to 13.0 +/- 1.0 h. Renal clearance for oxazepam glucuronide was significantly reduced from 74 +/- 2 ml min-1 to 46 +/- 3 ml min-1. In vitro, diflunisal, at concentrations of 125 to 1000 micrograms ml-1, significantly displaced oxazepam from its plasma protein binding, the free fraction of oxazepam increasing by 28 to 56%. The free fraction of oxazepam glucuronide, ex vivo, increased by 49 +/- 5% (n = 3) during concomitant diflunisal treatment. These data suggest that the observed interaction between oxazepam and diflunisal results from a presystemic displacement of oxazepam from its plasma protein binding sites by diflunisal and from an inhibition of the tubular secretion of oxazepam glucuronide by the glucuronides of diflunisal.     

Relative bioavailability of trimeprazine tablets investigated in man using HPLC with electrochemical detection

The stability, partition coefficient, plasma protein binding, red blood cell distribution, and whole blood concentrations of trimeprazine were investigated. Trimeprazine solution was stable for 6 months at -20 degrees C and 3.5 months at 40 degrees C. In whole blood trimeprazine was stable for 5 weeks at -20 degrees C, 24 h at 4 degrees C, 4 h at 25 degrees C and 1 h at 37 degrees C. The apparent hexane-water partition coefficient varied from 1.50 (at pH 4.83) to over 100 (at pH 10.54). The fraction bound to plasma protein exceeded 0.9 as estimated by equilibrium dialysis with correction for volume shift. The mean plasma/red blood cell concentration ratio was 1.17 and the mean red blood cell/plasma distribution coefficient was 8.65. Six healthy adult males received single 5 mg doses of trimeprazine in a syrup (5 mg in 10 ml) and tablets with at least two weeks between doses. Blood was collected for 48 h. The mean (+/- s.e.m.) times for peak blood concentrations were 3.5 +/- 0.22 h for the syrup and 4.5 +/- 0.43 h for the tablets. There were no significant differences in Cmax values. The overall mean (+/- s.e.m.) terminal phase half-life was 4.78 +/- 0.59 h. Mean (+/- s.e.m.) areas under the concentration time curves from 0 to infinity (AUC infinity) were 11.0 +/- 1.99 ng h-1 ml-1 and 7.67 +/- 1.05 ng h-1 ml-1 for syrup and tablets, respectively. The mean relative bioavailability for the tablets was approximately 70% with respect to the syrup.     

Pharmacokinetics of dipipanone after a single oral dose.

A single oral dose of Diconal (dipipanone HCl 10 mg, cyclizine HCl 30 mg) was given to six volunteers. The mean peak plasma dipipanone concentration was 29 ng ml-1, the time to peak plasma concentration was 1-2 h, the mean elimination half-life was 3.5 h and the mean AUC was 156 ng ml-1 min. Less than 1% of the dose was excreted in urine unchanged over 24 h.     

Effects of antacids and food on absorption of famotidine.

The effect of a high potency antacid and food on the bioavailability of famotidine was studied in 17 healthy volunteers in an open randomized three-way cross-over trial. After an overnight fast, famotidine was administered to each subject as follows: 40 mg famotidine orally alone; 40 mg orally with antacid; and 40 mg orally with a standard breakfast. Coadministration of the antacid caused a small but significant reduction in the maximum plasma concentration (Cmax) of famotidine from 81.1 +/- 54.2 to 60.8 +/- 21.6 ng ml-1 (P less than 0.05) and a small decrease in the area under plasma concentration-time curve [AUC] from 443.3 +/- 249.2 to 355.0 +/- 125.1 ng ml-1 h (P greater than 0.05). However, there was only a minimal effect of food on these parameters; the Cmax and [AUC] were 81.6 +/- 29.6 ng ml-1 and 434.8 +/- 145.9 ng ml-1 h, respectively.     

Bioavailability and cardiovascular safety of Dexatrim (phenylpropanolamine hydrochloride) from a controlled-release caplet

The bioavailability and pharmacokinetics of phenylpropanolamine hydrochloride (PPA HCl) from a Dexatrim controlled-release (CR) caplet and solution was studied. Each subject (n = 12) received either a 75 mg PPA HCl CR caplet once daily or a 25 mg PPA HCl solution given three times a day. All subjects received the medication for 4 consecutive days. On Day 1, the mean +/- SEM, AUC, tmax, and Cmax values were 1651 +/- 127 ng x h ml-1, 4.5 +/- 0.26 h and 143 +/- 13.5 ng ml-1, respectively, for the CR caplet and 1716 +/- 90.3 ng x h ml-1, 1.25 +/- 0.08 h and 126 +/- 5.8 ng ml-1 for the solution, respectively. At steady state (Day 4), the mean +/- SEM, AUC, tmax, and Cmax values were 1832 +/- 101 ng x h ml-1, 4.17 +/- 0.17 h and 151 +/- 6.5 ng ml-1, respectively, for the CR caplet and 2014 +/- 116 ng x h ml-1, 1.33 +/- 0.09 h and 143 +/- 8.7 ng ml-1, respectively, for the solution. The data from Day 1 were fitted to an oral one compartment model with a first order absorption rate constant, kA, first order elimination rate constant, k and lag time. The mean +/- SEM, kA, elimination half-life and lag time for PPA HCl from the CR caplet were 0.488 +/- 0.182 ng h ml-1, 5.84 +/- 1.66 h and 0.394 +/- 0.224 h, respectively. The mean +/- SEM, kA, elimination half-life and lag time for PPA HCl from the solution were 2.87 +/- 1.51 ng x h ml-1, 3.73 +/- 1.21 h, and 0.325 +/- 0.101 h, respectively. The smaller apparent kA and longer elimination half-life for PPA HCl from the CR caplet is due to the slow release of PPA HCl, thereby slowing its absorption producing sustained plasma drug concentrations. Blood pressures (supine and sitting) and heart rates measured at the time of blood sampling after the administration of the PPA HCl dosage forms demonstrated no clinically significant relationship between cardiovascular response and PPA HCl plasma concentration. These data demonstrate the bioavailability and pharmacokinetics of PPA HCl from a CR caplet and an immediate release solution.     

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.     

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.     

Population study of triazolam pharmacokinetics.

The kinetics of a single 0.5 mg oral dose of the triazolobenzodiazepine hypnotic triazolam, were studied in 54 healthy young men aged 20-44 years, with a mean body weight of 77 kg. Triazolam kinetics were determined from multiple plasma concentrations measured during 14 h post-dose. The overall mean +/- s.e. mean (with range) kinetic variables were: peak plasma concentration, 4.4 +/- 0.3 (1.7-9.4) ng ml-1; time of peak, 1.3 +/- 0.1 (0.5-4.0) h after dose; elimination half-life, 2.6 +/- 0.1 (1.1-4.4) h; total AUC: 19.1 +/- 1.1 (4.4-47.7) ng ml-1 h; oral clearance, 526 +/- 38 (175-1892) ml min-1. All kinetic variables were consistent with Poisson distributions, based on the Kolmogorov-Smirnov Goodness of Fit test. None of the variables fit normal distributions. Four of five were consistent with a log normal distribution. Peak plasma level was highly correlated with clearance (r = -0.85, P less than 0.0001), and AUC (r = 0.85, P less than 0.0001) but not with body weight (r = 0.21, NS). Clearance and body weight were not correlated (r = -0.01). Triazolam clearance may vary widely even within a homogeneous group of healthy young men.     

Bioavailability of terfenadine in man

Fourteen normal male subjects were given either 60mg or 180mg of terfenadine suspension in a randomized two-way crossover study. Peak plasma concentrations of 1.544 +/- 0.726 (mean +/- S.D.) ng ml-1 were obtained in 0.786 h following the 60 mg dose and displayed an AUC or 11.864 +/- 3.369 ng h ml-1. Whereas peak plasma concentrations of 4.519 +/- 2.002 ng ml-1 in 1.071 +/- 0.514 h were obtained following the 180 mg dose. The AUC following the 180 mg dose was 44.341 +/- 22.041 ng h ml-1. When 60 mg of 14C terfenadine was given to six additional subjects, the peak plasma concentrations of 351 +/- 43 ng equivalents per ml were obtained in 1.67 +/- 0.41 h and the AUC was 2297.71 +/- 310.85 ng-equivalents h ml-1. This indicates that approximately 99.5 per cent of the terfenadine related material that is absorbed undergoes biotransformation. Urinary excretion of 14C accounted for 39.89 +/- 5.29 per cent of the dose while 60.58 +/- 2.44 per cent of the dose was recovered in the feces in twelve days. Thin-layer chromatographic (TLC) examination of fecal extracts showed only a trace of material chromatographing with terfenadine. This may indicate that the 14C present in the feces is not due to lack of absorption.