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.     

Plasma and whole blood mefloquine concentrations during treatment of chloroquine-resistant falciparum malaria with the combination mefloquine-sulphadoxine-pyrimethamine.

Mefloquine-sulphadoxine-pyrimethamine (MSP) in combination has proved effective against multiple-drug-resistant falciparum malaria, but nothing is known about mefloquine absorption when it is given in this formulation. Nine Thai patients, aged 15-51 years with uncomplicated chloroquine-resistant falciparum malaria, took 11.2-16.7 mg of mefloquine base per kilogram bodyweight as MSP tablets. All patients responded to treatment with fever and parasite clearance times of 61 +/- 29 h (mean +/- s.d.) and 52 +/- 24 h, respectively. The mean apparent absorption half-time (t1/2abs) of mefloquine was 4.89 h (range 2.25-9.72) and mean peak plasma concentration was 1815 ng ml-1 (range 725-3368). Peak plasma mefloquine concentrations in three patients who vomited within 2 h of treatment were 725, 956 and 1972 ng ml-1. There was no significant difference between plasma and whole blood mefloquine concentrations during the first 48 h of treatment. Based on the elimination of parasitaemia, the plasma mefloquine concentrations are adequate for therapy of uncomplicated falciparum malaria although the relationship between plasma concentrations and therapeutic efficacy of mefloquine requires further study.     

Studies of mefloquine bioavailability and kinetics using a stable isotope technique: a comparison of Thai patients with falciparum malaria and healthy Caucasian volunteers.

1 A mefloquine hydrochloride tablet (250 mg base equivalent to 4.8 +/- 0.6 mg kg-1; mean +/- s.d.) and deuterium labelled mefloquine hydrochloride solution (250 mg base) were given to six adult male Thai patients with acute falciparum malaria and six healthy Swiss adult male volunteers (equivalent to 3.5 +/- 0.1 mg kg-1). 2 The relative bioavailability of the tablet formulation derived from comparison of the areas under the plasma concentration-time curves was similar in both groups; 87 +/- 11% and 89 +/- 10% (mean +/- s.d.). 3 The rate of drug absorption appeared to be similar in the two groups but peak plasma mefloquine concentrations were approximately three times higher in the Thai patients (1004 +/- 276 ng ml-1 for the tablet and 1085 +/- 280 ng ml-1 for the suspension) compared with the Swiss volunteers (319 +/- 73 ng ml-1 for the tablet, and 369 +/- 121 ng ml-1 for the suspension). 4 Estimates of the oral clearance CLpo of unlabelled mefloquine were significantly lower (17.5 +/- 4.4 ml h-1 kg-1) in the Thai patients compared with 28.8 +/- 3.5 ml h-1 kg-1 in the Swiss volunteers; P less than 0.05). Terminal elimination half-lives were significantly shorter in the patients (10.3 +/- 2.5 days) than in the volunteers (16.7 +/- 1.9 days; P less than 0.005). Differences of a similar magnitude were observed when comparing the pharmacokinetic parameters derived from the deuteromefloquine plasma concentrations. 5 Both genetic and disease related factors are likely to account for the large pharmacokinetic differences between the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetic and pharmacodynamic interactions of mefloquine and quinine

This study was carried out to investigate the pharmacokinetic and pharmacodynamic interactions between two antimalarial drugs, mefloquine and quinine. A randomized, comparative, three-way crossover study was performed in seven healthy male Thais after the administration of three drug regimens on three occasions i.e., a single oral dose of quinine sulfate (600 mg), mefloquine (750 mg) alone, or the combination of mefloquine (750 mg) and quinine (600 mg given 24 h after mefloquine). QTc interval was significantly prolonged in subjects following the combination regimen (at 2.5, 3, 4, 6, 8, 12, 18, 24 h after the quinine dose) but no abnormal clinical signs or symptoms were found. There were no significant changes in vital signs or routine laboratory values in any of the subjects. The pharmacokinetics of mefloquine and quinine were influenced by the presence of the other drug. Greater blood schizonticidal activities were collected from the sera of subjects on the combination regimen than from the sera of subjects the quinine or mefloquine regimens. The minimum inhibitory concentrations (MICs) of the equivalent concentrations (Eqs) of quinine or mefloquine, which completely inhibited the growth of the K1 strain of Plasmodium falciparum in vitro (MICs of quinine Eq and mefloquine Eq) were significantly lower in the sera of subjects on the combination regimens, than in the sera of subjects on mefloquine or quinine alone [MICs of quinine Eq: 41.2 (21.25-73.5) vs. 135 (118-150) ng/ml; MICs of mefloquine Eq: 18.2 (17-19.2) vs. 25.2 (24.4-26.8) ng/ml].     

Population pharmacokinetic and pharmacodynamic modelling of artemisinin and mefloquine enantiomers in patients with falciparum malaria

OBJECTIVES: The aims of this study were to investigate whether artemisinin influences the pharmacokinetics of mefloquine enantiomers or vice versa and to model the antiparasitic effect of these drugs alone and in combination in Plasmodium falciparum malaria patients. METHODS: Forty-two male and female patients were randomised to treatment with either oral artemisinin 500 mg daily for 3 days followed by oral mefloquine 750 mg on day 4, oral artemisinin 500 mg daily for 3 days plus oral mefloquine 750 mg on day 1 or a single 750-mg oral dose of mefloquine. The data was modelled using NONMEM. RESULTS: All patients were successfully treated regardless of treatment. The fastest parasite clearance rates were observed in patients receiving artemisinin together with mefloquine on the first day of treatment. A pharmacodynamic model based on the life cycle of P. falciparum successfully described the efficacy of artemisinin, mefloquine and the combination. The time artemisinin concentration stays above a minimum inhibitory concentration was estimated to 2.97 h (relative standard error 4.7 h). The two mefloquine enantiomers exhibited different pharmacokinetics, with an oral clearance of 3.51 (7.9) l/h and 0.602 (6.9) l/h for RS-mefloquine and SR-mefloquine, respectively. In patients receiving only artemisinin the first 3 days, artemisinin oral clearance was 6.9-fold higher the last day of treatment compared with the first day. There was no difference in the pharmacokinetics of mefloquine enantiomers when mefloquine was given alone, in combination with artemisinin or after a 3-day regimen of artemisinin. There was a tendency towards, although non-significant, higher artemisinin concentrations when artemisinin was given together with mefloquine compared with when given alone. CONCLUSIONS: No significant pharmacokinetic interactions were observed after co-administration of artemisinin and mefloquine. The P. falciparum malaria pharmacodynamic model successfully described the antimalarial effect of artemisinin, mefloquine and a combination of the two drugs.     

Age-related changes in the pharmacokinetics and pharmacodynamics of nifedipine.

1. The effects of age on the pharmacology of nifedipine were investigated in 11 young and six elderly normotensive volunteers. 2. Following 2.5 mg of nifedipine i.v. the plasma clearance of nifedipine was 348 +/- 83 (s.d.) ml min-1 in the elderly compared with 519 +/- 125 ml min-1 in the young (P less than 0.05) and the AUC in the elderly was significantly greater at 125 +/- 28 ng ml-1 h compared with 83.9 +/- 19 ng ml-1 h (P less than 0.05). The Vss was similar in both age groups. 3. Following 10 mg oral sustained release nifedipine the AUC was 281 +/- 64 ng ml-1 h in the elderly compared with 136 +/- 56 ng ml-1 h in the young (P less than 0.002) and Cmax in the elderly was significantly greater at 36.8 +/- 11.8 ng ml-1 compared with 22.3 +/- 5.8 ng ml-1 (P less than 0.05). The trend towards an increased bioavailability in elderly subjects (36%) was supported by a significantly lower nitropyridine metabolite/nifedipine ratio in the elderly. 4. Absorption rate limited kinetics of the sustained release formulation were indicated by the prolonged t1/2 compared with i.v. administration. In the elderly t1/2 (oral) was significantly greater than in the young (elderly 6.7 +/- 2.2 h, young 3.8 +/- 1.4 h, P less than 0.05). 5. Haemodynamic changes in the young were confined to a tachycardia following i.v. administration. In the elderly, supine BP fell significantly following both oral and i.v. nifedipine while the heart rate remained unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)     

Mefloquine antimalarial prophylaxis in pregnancy: dose finding and pharmacokinetic study.

1. A dose finding pharmacokinetic study was performed in 20 Karen women in the third trimester of pregnancy receiving antimalarial prophylaxis with mefloquine. Ten received 250 mg mefloquine base weekly and ten received identical tablets of 125 mg base/week. 2. Both dose regimens were well tolerated. Malaria was prevented effectively, there were no serious adverse effects, all pregnancies proceeded normally, and there were no abnormalities in the babies followed up to 2 years. 3. The median time from dose administration to peak whole blood mefloquine concentration was 6 (range 3-24) h. Mean (+/- s.d.) peak and trough concentrations in the seventh week were 722 +/- 279 and 488 +/- 155 ng ml-1 with the 250 mg/week dose, and 390 +/- 81 and 185 +/- 53 ng ml-1 with the 125 mg/week dose regimens respectively. These blood concentration values are lower than those reported previously in non-pregnant adults. 4. One and two compartmental models were fitted to the whole blood concentration-time data. Mean (+/- s.d.) clearance (CL/F) was 0.78 +/- 0.27 ml min-1 kg-1, and the apparent terminal elimination half-life (t1/2) was 11.6 +/- 7.9 days. 5. Further studies to determine the oral bioavailability of mefloquine are needed, but these results suggest that clearance may be increased in late pregnancy. These preliminary results of good efficacy without significant toxicity are encouraging, and a more extensive evaluation of mefloquine antimalarial prophylaxis in pregnancy is now warranted.     

Disposition of the antimalarial, mefloquine, in the isolated perfused rat liver

The disposition of mefloquine has been investigated in the isolated perfused rat liver (IPRL) preparation after the administration of [14C]mefloquine HCl (3.8 mg, 4 microCi, quinoline ring labeled). Mefloquine underwent avid hepatic uptake within 10 min of dosing. Also at this point, hepatic oxygen consumption was reduced markedly in four of the six IPRL preparations, but was restored completely by approximately 30 min post-dose. The drug concentration profile underwent a biexponential decline over the 4-hr study period, with a terminal T1/2 of 1.0 +/- 0.3 hr. The area under the perfusate plasma concentration/time curve (AUC0-infinity) was 4.0 +/- 1.8 micrograms.hr.ml-1. Mefloquine was a high clearance compound (956.0 +/- 390 ml/hr) with a large apparent volume of distribution (1416 +/- 819 ml) in the IPRL. Biliary excretion accounted for 7.5 +/- 6.5% of the dose. Mefloquine was quantitated by HPLC analysis as approximately half (3.3 +/- 1.8%) of biliary label, the remainder consisting of highly polar metabolites of mefloquine. By 4 hr, a total of 64.8 +/- 4.4% of the [14C] dose was recovered from the livers. Subsequent HPLC analysis revealed this to be mostly unchanged mefloquine. Subcellular fractionation of the homogenized livers revealed that 50.6 +/- 6.8% of the dose of mefloquine was located in the 10,000 g pellet. In summary, mefloquine was cleared rapidly from the IPRL and underwent avid hepatic uptake into the lipid-rich fractions of rat liver.     

Clinical pharmacokinetics of the nifedipine/co-dergocrine combination in impaired liver and renal function.

Following a single oral dose of 20 mg nifedipine combined with 2 mg co-dergocrine to 24 subjects, the pharmacokinetics of this drug were studied. 8 normotensive subjects had normal renal and hepatic function, 8 patients had chronic renal insufficiency (creatinine clearance less than 30 ml.min-1) and 8 patients had liver cirrhosis which was confirmed by liver biopsy. The area under the plasma level time curve (AUC infinity) of co-dergocrine increased from 0.59 +/- 0.41 ng.ml-1. (mean +/- SD) in the normals to 1.24 +/- 0.95 ng.ml-1.h in liver cirrhosis (P less than 0.05) and to 1.81 +/- 0.9 ng.ml-1.h in renal failure (P less than 0.05 compared with the control group). Corresponding values for the nifedipine AUC infinity were 564.5 +/- 268 ng.ml-1.h, 1547.5 +/- 1134 (P less than 0.05) and 929 +/- 533 ng.ml-1.h (P less than 0.05; gas chromatographic method). The incidence of adverse effects was lower in patients with renal failure than in subjects with normal renal and liver function as well as in those with liver cirrhosis.     

A comparison of the pharmacokinetics of mefloquine in healthy Thai volunteers and in Thai patients with falciparum malaria

Summary We have studied the kinetics of a single oral dose of mefloquine (750 mg) in 12 Thai patients with falciparum malaria and have compared the results with those of a previous study in 12 healthy Thai volunteers [6].All the patients responded to treatment with a mean parasite clearance time of 66.6 h and a mean fever clearance time of 54.1 h.There was no significant difference in peak plasma concentration, time to peak, area under the curve or apparent volume of distribution between patients and controls. However, the terminal half-life (t_1/2) and mean residence time (MRT) were shorter in the patients (12.2 vs 16.7 days for t_1/2 and 15.5 vs 21.4 days for MRT).We conclude that there are changes in the disposition of mefloquine related to malaria, although the exact basis of the changes is not clear.     

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.     

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.     

Effect of rifampin on plasma concentrations of mefloquine in healthy volunteers

Mefloquine is a 4-quinolinemethanol compound structurally related to quinine. Quinine is mainly metabolized by the cytochrome P450 3A4 isozyme (CYP3A4), whereas rifampin, a potent inducer of CYP3A4, is known to markedly decrease plasma quinine concentration. Our aim was to study the effect of rifampin on the pharmacokinetics of mefloquine, and explore a possible role of CYP3A4 on mefloquine metabolism. In an open, two-phase crossover study, seven healthy Thai male volunteers received a single oral dose of 500 mg mefloquine alone, or 500 mg mefloquine plus a long-term administration of 600 mg rifampin. Blood samples were collected at specific time points over a 56-day period. Plasma mefloquine and its carboxylic acid metabolite were measured by HPLC for pharmacokinetic analysis. The results indicate that rifampin significantly decreased the area under the plasma concentration-time curve (AUC0 - infinity) of mefloquine by 68% (P < 0.01), maximum plasma concentration (Cmax) by 19% (P < 0.001), and elimination half-life (t1/2) by 63% (P < 0.01), whereas the time to reach Cmax (t(max)) of mefloquine was unaffected. The apparent oral clearance (CL) of mefloquine was significantly increased by 281% (P < 0.01). After administration of rifampin, the Cmax of the carboxylic acid metabolite of mefloquine was significantly increased by 47% (P < 0.05), whereas the t1/2 was significantly decreased by 39% (P < 0.01), and t(max) by 76% (P < 0.01). The AUC0 - infinity and CL of the mefloquine metabolite were increased by 30% and 25%, respectively, but were not significantly different from the control phase. The results indicate that rifampin reduces the plasma concentration of a single oral dose of 500 mg mefloquine by increasing metabolism of mefloquine in the liver and gut wall. The CYP3A4 isozyme most likely plays an important role in the enhanced metabolism of mefloquine. Simultaneous use of rifampin and mefloquine should be avoided to optimize the therapeutic efficacy of mefloquine and prevent the risk of Plasmodium falciparum resistance in malarial treatment.     

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)     

The effect of age on the pharmacokinetics of levodopa administered alone and in the presence of carbidopa.

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

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.     

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 pharmacokinetics of perindopril in patients with liver cirrhosis.

Perindopril is a non-sulphydryl angiotensin converting enzyme (ACE) inhibitor which requires hydrolysis to its active metabolite, perindoprilat, to produce its effects. Ten cirrhotic patients with mild to severe disease were studied after oral administration of a single 8 mg dose of perindopril as its tert-butylamine salt. Compared with a historical control group of young healthy volunteers receiving the same single oral dose of perindopril, mean AUC values of the prodrug perindopril were double in patients with liver cirrhosis (602 +/- 294 s.d. ng ml-1 h vs 266 +/- 70 s.d. ng ml-1 h) whereas the mean AUC of perindoprilat was found to be similar (134 +/- 139 ng ml-1 h vs 120 +/- 29 ng ml-1 h). The partial metabolic clearance of perindopril to perindoprilat was much lower in the cirrhotics (26 +/- 12 ml min-1 vs 58 +/- 22 ml min-1). The maximum inhibition of plasma ACE activity measured in the cirrhotic patients (87.5 +/- 5.1%) was comparable with that previously reported with perindopril in patients with mild hepatic impairment as well as in patients with essential hypertension. We suggest that liver cirrhosis may be associated with imparied deesterification of perindopril to its active metabolite perindoprilat but that no dosage adjustment of perindopril is required in cirrhotic patients.     

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.     

Accuracy and clinical utility of simplified tests of antipyrine metabolism.

High-performance liquid chromatography (h.p.l.c.) was used to measure plasma antipyrine concentrations in sixteen healthy subjects; five males, six females taking oral contraceptive steroids (OCS) and five age-matched females not taking OCS. Following oral administration of the drug, antipyrine clearance could be determined with similar precision and accuracy from plasma concentrations at two selected times (4 h and 24 h) ('two-sample antipyrine clearance test') as from six samples taken over two to three elimination half-lives (t1/2) of the drug ('conventional antipyrine clearance test'). Provided times for plasma sampling were modified appropriately, the two-sample antipyrine clearance test also gave reliable results in four patients taking phenytoin (sampling times 4 h and 8 h) who had significantly enhanced antipyrine clearance, and in nine patients with severe liver disease (using 4 h and 48 h) in whom antipyrine clearance was impaired. Urinary excretion of antipyrine metabolites (from 0-24 h) was determined in the above groups. Antipyrine systemic clearance correlated best with the percentage of administered dose excreted as 4-hydroxyantipyrine (r = 0.66, P less than 0.001) but also with 3-hydroxymethylantipyrine (r = 0.54, P less than 0.001) and with total metabolites excreted (r = 0.60, P less than 0.001). Total antipyrine metabolites excreted in urine in 24 h were significantly different from controls only in patients with liver disease (14 +/- 7.6% of administered dose vs 62 +/- 14%, P less than 0.001). The relative proportion of antipyrine metabolites did not appear to be altered when hepatic mixed function oxidation was induced by phenytoin or inhibited by OCS or by severe liver disease.