Comparison of the bioavailability of 250 and 500 mg divalproex sodium extended-release tablets in healthy volunteers

Divalproex sodium extended-release tablet (divalproex-ER), 500 mg strength, is approved for use in the prophylaxis of migraine headaches and epilepsy. The bioavailability of novel 250 mg divalproex-ER formulations, under development to allow greater flexibility in dosing, was compared with the available 500 mg divalproex-ER in a single-dose, fasting and nonfasting, randomized, open-label, crossover study in healthy adult volunteers. One group of 15 subjects was dosed after a 10 h overnight fast and another group of 24 subjects was dosed after a high-fat breakfast. Plasma valproic acid concentration-time profiles were used to assess pharmacokinetics. Bioequivalence assessments were made via the 90% confidence interval for maximum plasma valproic acid concentration (C(max)) and the area under the concentration-time curve from time zero to infinity (AUC(infinity)). The relative bioavailability point estimates (90% confidence interval) for C(max) and AUC(infinity) were 1.05 (0.94-1.16) and 0.95 (0.83-1.09) under fasting conditions, and 1.01 (0.91-1.12) and 0.97 (0.87-1.08) under nonfasting conditions, respectively. The test 250 mg tablet formulation was bioequivalent to the reference 500 mg tablet formulation, under both fasting and nonfasting conditions, as the 90% confidence intervals for both C(max) and AUC(infinity) were within the 0.80-1.25 interval.     

Absorption and disposition including enterohepatic circulation of (14C) roquinimex after oral administration to healthy volunteers

The absorption and disposition of roquinimex (Linomide) were studied in four male and two female healthy volunteers. The subjects received a single oral aqueous solution of 14C-labelled roquinimex, about 0.1 mg/kg, after an overnight fast. Blood samples were taken and urine and faeces were collected for 10 days after dosing. The plasma, urine and faeces concentrations of roquinimex and metabolites were determined by high-performance liquid chromatography (HPLC) with radiochemical detection. The metabolites were identified by HPLC-mass spectroscopy (MS). The plasma concentration-time profiles of roquinimex exhibited a rapid absorption followed by a bi-exponential disposition. A secondary peak was observed between 6 and 8 h, indicating enterohepatic circulation (EHC) of roquinimex. The terminal disposition half-life was estimated as 27 h. The primary metabolic pathways of roquinimex were hydroxylation, demethylation and conjugation. The major compound in plasma was roquinimex; metabolites were only occasionally detected. In urine and faeces, roquinimex accounted for 2% of the dose and conjugated and hydroxylated metabolites each accounted for about 30% of the dose. A model was derived for the plasma concentrations of roquinimex and the amount of urinary excreted roquinimex to take into account EHC. This model improved the goodness-of-fit according to common goodness-of-fit criteria. The values of the pharmacokinetic parameters were similar using compartmental and non-compartmental methods, indicating that the contribution of EHC of roquinimex is of minor importance in the evaluation of the pharmacokinetics of roquinimex.     

Determination of the bioavailability of [14C]-hexaminolevulinate using accelerator mass spectrometry after intravesical administration to human volunteers

Hexaminolevulinate (HAL) is a diagnostic agent that allows the visualization of tumor tissue in the bladder by fluorescence cystoscopy. It is administered intravesically via a catheter for 1 hour, followed by blue light bladder inspection to induce selective red tumor fluorescence. Hexaminolevulinate should ideally be confined to the bladder only, but it is likely that some absorption occurs during administration, and therefore the systemic bioavailability is of interest. The bioavailability of HAL was determined by intravesical and intravenous administration of [14C]-HAL hydrochloride to 8 human volunteers. To reduce the radiation dose as low as possible, the ultrasensitive analytical technique of accelerator mass spectrometry was used to measure [14C]-HAL. The bioavailability of [14C]-HAL after intravesical and intravenous administration was determined from the respective area under the curve based on total radioactivity and was determined to be 7% (range, 5%-10%; 90% confidence interval). The systemic absorption of [14C]-HAL after intravesical administration is low and supports previous clinical experience with HAL showing no systemic side effects.     

Bioequivalence evaluation of two brands of cefuroxime 500 mg tablets (Cefuzime and Zinnat) in healthy human volunteers

A bioequivalence study of two oral formulations of 500 mg cefuroxime axetil was carried out in 24 healthy volunteers following a single dose, standard two-treatment cross-over design at the College of Pharmacy, King Saud University, Riyadh, Saudi Arabia, working jointly with King Khalid University Hospital. The two formulations used were Cefuzime (Julphar, United Arab Emirates) as the test and Zinnat (Glaxo Wellcome, England) as the reference product. Both test and reference tablets were administered to each subject after an overnight fasting on two treatment days separated by a 1-week washout period. After dosing, serial blood samples were collected for a period of 8 h. Plasma harvested from blood was analysed for cefuroxime by a sensitive, reproducible and accurate high pressure liquid chromatography (HPLC) method. Various pharmacokinetic parameters including AUC(0-t), AUC(0-infinity), C(max), T(max), T(1/2) and K(el) were determined from plasma concentrations of both formulations and found to be in good agreement with reported values. AUC(0-t), AUC(0-infinity) and C(max) were tested for bioequivalence after log-transformation of data. No significant difference was found based on an analysis of variance (ANOVA); 90% confidence interval for test/reference ratio of these parameters were found within bioequivalence acceptance range of 80-125%. Based on these statistical inferences, it was concluded that Cefuzime is bioequivalent to Zinnat.     

The application of accelerator mass spectrometry to absolute bioavailability studies in humans: simultaneous administration of an intravenous microdose of 14C-nelfinavir mesylate solution and oral nelfinavir to healthy volunteers

The absolute bioavailability of nelfinavir was determined in 6 healthy volunteers following simultaneous administration of 1250 mg oral nelfinavir and an intravenous infusion of (14)C-nelfinavir mesylate on day 1 and at steady state. Nelfinavir oral bioavailability decreased from 0.88 to 0.47 over the 11-day study period. The moderate bioavailability of nelfinavir was due to significant first-pass metabolism rather than low absorption, limiting the potential of formulation improvement to decrease pill burden. Human absolute bioavailability studies with accelerator mass spectrometry microdosing, in which an intravenous microdose is given along with a conventional oral dose of the same drug, can differentiate between gastrointestinal absorption and the first-pass metabolism of new drug candidates. Accelerator mass spectrometry allowed a several thousand-fold dose reduction of (14)C-nelfinavir relative to that required for liquid scintillation counting. Accelerator mass spectrometry microdosing reduces potential safety issues around dosing radioactivity to humans and prevents the need to formulate high intravenous doses.     

Bioequivalence evaluation of two brands of metformin 500 mg tablets (Dialon & Glucophage)--in healthy human volunteers

A randomized, two-way, crossover study was conducted in 24 fasting, healthy, male volunteers to compare the bioavailability of two brands of metformin 500 mg tablets; Dialon (Julphar, UAE) as test and Glucophage (Lipha Pharmaceutical Industries, France) as reference product. The study was performed at the International Pharmaceutical Research Centre (IPRC), in joint venture with Al-Mowasah Hospital, Amman, Jordan. The drug was administered with 240 ml of water after a 10-h overnight fasting on two treatment days separated by 1-week washout period. After dosing, serial blood samples were collected for a period of 30 h. Plasma harvested from blood was analyzed for metformin by validated HPLC method with UV-visible detector capable to detect metformin in the range of 0.05-5.0 microg/ml with limit of quantitation of 0.05 microg/ml. Various pharmacokinetic parameters including AUC(0-t), AUC(0-proportional to), C(max), T(max), T(1/2), and lambda(Z) were determined from plasma concentrations of both formulations and found to be in good agreement with reported values. AUC(0-t), AUC(0-proportional to) and C(max) were tested for bioequivalence after log-transformation of data. No significant difference was found based on ANOVA; 90% confidence interval (97.9-110.8% for AUC(0-t), 97.4-110.7% for AUC(0-proportional to); 95.3-110.5% for C(max)) of test/reference ratio for these parameters were found within bioequivalence acceptance range of 80-125%. Based on these statistical inferences, it was concluded that Dialon is bioequivalent to Glucophage.     

Concentrations in plasma, urinary excretion and bactericidal activity of levofloxacin (500 mg) versus ciprofloxacin (500 mg) in healthy volunteers receiving a single oral dose

In a randomised crossover study, 14 volunteers received a single oral dose of 500 mg levofloxacin or 500 mg ciprofloxacin in order to assess plasma concentrations by high-pressure liquid chromatography (up to 24 h), urinary excretion and urinary bactericidal titres (UBTs) at intervals up to 120 h. The median maximum concentration of levofloxacin in plasma was 6.1 mg/L and that of ciprofloxacin was 2.3 mg/L. The median cumulative level of renal excretion of the administered dose of the parent drug was 81.2% for levofloxacin and 36.2% for ciprofloxacin. UBTs were determined for a reference strain and nine clinical uropathogens. The median UBTs of both quinolones measured within the first 12 h were between 0 and 1:≥1024, correlating with the minimum inhibitory concentrations (MICs) of the strains. For Gram-negative strains, the UBTs of both quinolones were comparable despite the lower MICs of ciprofloxacin. During further time courses, however, the UBTs of levofloxacin were significantly higher than those of ciprofloxacin. For Gram-positive strains, for which the MICs of levofloxacin were equal to or lower than those of ciprofloxacin, the UBTs of levofloxacin were already significantly higher from the beginning. It can be concluded that overall the doses of the two tested fluoroquinolones may be considered equivalent with regard to treatment of complicated urinary tract infections, although the recommended dosing is twice daily for ciprofloxacin and once daily for levofloxacin.     

Urinary bactericidal activity, urinary excretion and plasma concentrations of gatifloxacin (400 mg) versus ciprofloxacin (500 mg) in healthy volunteers after a single oral dose

In an open randomised double-crossover study 12 volunteers (six men, six women) received a single oral dose of gatifloxacin (400 mg) or ciprofloxacin (500 mg) to assess urinary bactericidal activity (in eight intervals up to 120 h) and pharmacokinetic (PK) parameters (up to 36 h). Plasma concentrations and urinary excretion were determined by HPLC with fluorescence detection, and urinary bactericidal titers (UBT) by microdilution-method, using antibiotic-free urine of each volunteer. The mean maximum plasma concentration of gatifloxacin was 3.35 mg/l and that of ciprofloxacin 2.12 mg/l. The mean (median) cumulative renal excretion of the parent drug was for gatifloxacin 81 (83)% of the administered dose within 120 h and for ciprofloxacin 43 (45)%. The UBTs, i.e. the highest two-fold dilution (antibiotic-free urine as diluent) of urine still being bactericidal, were determined for an Escherichia coli ATCC reference strain and nine clinical uropathogens with the following MICs (mg/l) for gatifloxacin/ciprofloxacin (microdilution, MHB): E. coli ATCC 25922 (0.008/0.008); E. coli 523 (0.06/0.06); Klebsiella pneumoniae 1058 (0.03/0.016); Proteus mirabilis 524 (0.125/0.016); Pseudomonas aeruginosa 561 (1/0.125); Enterococcus faecalis strains 60 an 55 (0.5/1 and 8/32); Staphylococcus aureus strains 248 and 596 (both 0.03/0.125) and S. saprophyticus Ho94 (0.125/0.25). The median UBTs measured within the first 6h for gatifloxacin were between 1:16 and 1:>or=1024 for the Gram-negative strains including P. aeruginosa and between 1:8 and 1:>or=1024 for the five Gram-positive strains. The median UBTs for ciprofloxacin were between 1:64 and 1:>or=1024 for the Gram-negative strains (incl P. aeruginosa) and between 1:1.5 and 1:768 for the five Gram-positive strains. The UBTs up to 12 < 0.05 h showed no difference (P<0.05 ) for both E. coli strains, but ciprofloxacin was superior to gatifloxacin against Klebsiella, Proteus and Pseudomonas strains and gatifloxacin was superior to ciprofloxacin against all Gram-positive strains. For the UBTs at 12-24 h, gatifloxacin was generally superior to ciprofloxacin, but showed no difference in the Proteus and Pseudomonas strains. The areas under the UBT-time-curve (AUBT) up to 120 h showed statistically significant (P ) differences between both quinolones in favour of gatifloxacin against 8 of 10 strains tested, no difference for P. mirabilis and significantly higher activity of ciprofloxacin against P. aeruginosa. In conclusion, gatifloxacin and ciprofloxacin had overall comparable initial urinary bactericidal activity with some differences for specific pathogens, some times in favour of gatifloxacin (Gram-positives) and some times of ciprofloxacin (usually Gram-negatives), suggesting that for empiric therapy a single oral dose of gatifloxacin (400mg) would be clinically equivalent to ciprofloxacin (500 mg) twice daily-in agreement with the results of a clinical study in complicated UTI performed previously [Int. J. Antimicrob. Agents (2004)].     

Pharmacokinetics of mifentidine after single and multiple oral administration to healthy volunteers.

1. The pharmacokinetics of mifentidine, a new long acting histamine H2-receptor antagonist, were studied using two protocols. 2. In one study, on 5 different days six normal male subjects were given 2.5, 5, 10, or 20 mg mifentidine or placebo orally 60 min before starting a 3 h continuous gastric aspiration during which time blood samples were taken for measurement of mifentidine concentration. 3. The area under the curves of mifentidine plasma levels (AUC) vs time for the four doses was linearly related to the dose for each individual subject (r = 0.972, P less than 0.001). After doses of 2.5, 5, 10 and 20 mg, mifentidine reduced hydrogen ion output by respectively 36, 37, 60 and 75% and secretory volume by 1, 17, 40, and 47%. The effects at the two highest doses were statistically significant. AUC was correlated positively with the percentage reduction in hydrogen ion output (r = 0.802, P less than 0.001) and volume (r = 0.834, P less than 0.001) over a 3 h period. 4. In the second study, the pharmacokinetics were evaluated after once-daily treatment for 14 days in seven subjects given 10 mg and in seven others subjects given 20 mg. 5. After multiple dosing, renal clearance was similar for the two doses (11.6 +/- 2.11 l h-1 for the low dose and 17.0 +/- 2.0 l h-1 for the high dose). Plasma half-life (t1/2 lambda 2) was 16.0 +/- 3.0 h after the 10 mg dose and 11.9 +/- 1.2 h after 20 mg.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of dimetindene after intravenous and oral administration to healthy volunteers

The pharmacokinetics of dimetindene (dimethindene maleate, Fenistil, CAS 3614-69-5) were studied after its intravenous and oral administration to 8 healthy male volunteers. Serum concentrations were measured for 48 h using an enzyme-linked immunosorbent assay. Pharmacokinetic parameters (AUC, t1/2, CLs, Vd and F) were calculated using the clearance approach.     

Pharmacokinetics, excretion, and mass balance of 14C after administration of 14C-cholesterol-labeled AmBisome to healthy volunteers

Amphotericin B (AmB) in small unilamellar liposomes (AmBisome) provides higher plasma concentrations and greater safety than the conventional deoxycholate formulation. The authors compared the disposition of the liposome's drug and cholesterol components by measuring AmB and radioactivity in plasma, urine, and feces for 1 week after a single 2-hour infusion of 14C-cholesterol-labeled AmBisome (2 mg/kg, 1 microgCi/kg) in healthy adults (4 males, 1 female). The plasma profile of 14C-cholesterol differed from that of AmB, lacking an initial rapid disappearance phase, having a lower total clearance, and having a volume of distribution (0.13 L/kg) close to that of the plasma compartment. The biphasic disappearance and long plasma half-life (147 h) of 14C-cholesterol were similar to those of other low-clearance liposomes. This and the low clearance of 14C-cholesterol from the plasma compartment suggest that it served as a liposome marker. The plasma drug-lipid ratio fell during the study, showing that AmB was cleared from plasma more rapidly than cholesterol or liposomes and suggesting that the composition of the liposomes changed over time. 14C-radioactivity was recovered mainly in the feces (9.5% of dose), consistent with the catabolism of cholesterol to bile salts. Combined fecal and renal clearances were < 18% of total clearance, suggesting that most of the liposomal drug and lipid remained in the body 1 week after dosing. Thus, AmBisome remains in the circulation for an extended period of time while releasing AmB, resulting in its markedly altered pharmacokinetic and safety profiles.     

Bioequivalence study of bromhexine by liquid chromatography-electrospray ionization-mass spectrometry after oral administration of bromhexine hydrochloride tablets

A simple, sensitive and specific liquid chromatography-electrospray ionization-mass spectrometry method was developed for the quantitative determination of bromhexine in human plasma. Sample preparation involved simple liquid-liquid extraction. Simvastatin was used as internal standard. The separation of the analyte, internal standard and possible endogenous compounds were accomplished on a Shim-pack ODS column (150 mm x 4.6 mm i.d., 5 microm) with methanol-water (98:2, v/v) as mobile phase. Detection was performed in positive selected ion monitoring (SIM) mode at m/z 264.1 (for bromhexine) and m/z 441.7 (for IS). The method was validated over the range of 0.5-60 ng/mL and the results were acceptable. The method could offer the advantages of shorter run time (5.5 min) and lower LLOQ (0.5 ng/mL) with a decreased plasma volume requirement (250 microL) and it had been successfully applied to a bioequivalence study in healthy Chinese volunteers after single oral administration of 16 mg bromhexine.     

Pharmacokinetics of moxisylyte in healthy volunteers after intravenous and oral administration.

The concentration-time profiles of metabolites of moxisylyte, an alpha-blocking agent, in the plasma and urine of 12 healthy volunteers were investigated after intravenous (iv) and oral (two formulations) administration. The study was conducted with an open, randomized Latin squares design. Plasma and urine levels of moxisylyte and its biotransformation products were assayed by a specific HPLC method with fluorescence detection. Plasma levels declined in a monophasic or biphasic pattern depending on the subject. Two metabolites, conjugated desacetylmoxisylyte (DAM) and conjugated monodesmethylated DAM (MDAM), were found in plasma and urine. Unconjugated DAM was found in plasma only after iv administration. The apparent elimination half-lives of unconjugated DAM, conjugated DAM, and MDAM were 0.86, 1.7, and 3 h, respectively. The total amounts of metabolites (expressed as the equivalent of DAM) excreted in the urine were 75% after i.v. administration and 68 and 69% after oral administration of the two formulations. Oral absorption appeared to be complete for the two treatments. There was no statistical difference between the two oral formulations studied.     

中国汉族和朝鲜族健康志愿者单剂量口服氟康唑片的药物动力学考察

目的研究汉族和朝鲜族健康志愿者单剂量口服氟康唑片的药物动力学。方法健康汉族和朝鲜族受试者各10名,男女各半,口服氟康唑片200 mg,定时采血,用RP-HPLC法测定血药质量浓度,用drug and statistics(DAS 2.0.1)软件程序进行数据处理,用SPSS软件程序进行统计分析。结果汉族和朝鲜族受试者主要药物动力学参数ρmax为(4.91±0.67)、(4.70±0.86)mg.L-1;tmax为(1.90±0.90)、(2.55±1.07)h;t1/2为(33.07±5.90)、(31.02±6.02)h;AUC(0-96)为(189.61±32.91)、(183.75±31.83)mg.h.L-1,AUC(0-∞)为(219.21±40.46)、(209.93±46.37)mg.h.L-1。统计结果显示两民族受试者主要药物动力学参数差异无统计学意义。结论汉族、朝鲜族两民族的种族差异对氟康唑片的药物动力学无影响。     

Pharmacokinetics of ciprofloxacin XR (1000 mg) versus levofloxacin (500 mg) in plasma and urine of male and female healthy volunteers receiving a single oral dose

The new extended-release formulation of ciprofloxacin (ciprofloxacin XR) was designed for once-daily administration in the treatment of urinary tract infection (UTI). The aim of this study was to compare concentrations in plasma, urinary excretion (UE) and pharmacokinetic parameters of ciprofloxacin XR (1000 mg) versus those of levofloxacin (500 mg) in healthy volunteers receiving a single oral dose. In this randomised crossover study, 12 volunteers (6 males, 6 females) received a single oral dose of 1000 mg ciprofloxacin XR or 500 mg levofloxacin to assess the concentrations (by high-pressure liquid chromatography) in plasma up to 32 h and the UE at intervals up to 36 h. The following pharmacokinetic parameters were studied: C(max), t(max), t(1/2), AUC(plasma0-->infinity), AUC(plasma0-->last), Cl(ren), maximal urinary concentration (U(max)), AUC(urine0-->last) and UE. Both fluoroquinolones were well tolerated. The plasma concentrations of levofloxacin were significantly higher than those of ciprofloxacin XR throughout the study period. The urinary concentrations of ciprofloxacin XR were significantly higher than those of levofloxacin in the first collection interval (0-4 h), whereas the concentrations of levofloxacin were significantly higher than those of ciprofloxacin XR in the five last collection intervals (12-36 h). The median proportions of cumulative renal excretion of the administered dose of the parent drug up to 36 h were 43.1% for ciprofloxacin XR (range, 13.7-50.8%; mean +/- standard deviation (S.D.), 40.5 +/- 9.9%) and 79.8% for levofloxacin (range, 74.0-88.2%; mean +/- S.D., 80.4 +/- 5.5%). C(max), AUC(plasma0-->infinity), AUC(plasma0-->last) and UE were statistically significantly higher in the levofloxacin than in the ciprofloxacin XR phase; t(max), Cl(ren) and U(max) were statistically significantly higher in the ciprofloxacin XR phase than in the levofloxacin phase; and AUC(urine0-->last) and t(1/2) were not statistically different. After an oral administration of ciprofloxacin XR 1000 mg and levofloxacin 500 mg, C(max) and AUC(plasma0-->infinity) were significantly higher in the levofloxacin phase. UE of ciprofloxacin XR 1000 mg once daily, however, was equivalent to that of levofloxacin 500 mg, and overall comparable urinary concentrations and AUC(urine) were reached by both drugs. Therefore, it can be assumed that the two doses investigated can be considered equivalent for the treatment of UTI.     

单剂量口服匹伐他汀钙片在中国健康志愿者的药代动力学和安全性

目的 研究国产匹伐他汀钙片(降血脂药)在中国健康志愿者体内单次给药的药代动力学特征及安全性.方法 选择中国健康受试者12例,按3×3拉丁方设计,分别单次给予匹伐他汀钙片1,2,4 mg后,采用液相色谱-串联质谱联用法测定不同时间血中匹伐他汀的浓度,以DAS 2.0软件进行数据处理,求算药代动力学参数.结果 3个不同剂量组匹伐他汀的主要药代动力学参数:t_(1/2β)分别为(11.39±7.66),(10.00±7.30),(11.30±7.95)h;t_(max)分别为(0.83±0.29),(0.73±0.20),(0.85±0.46)h;C_(max)分别为(30.48±11.66),(60.80±22.97),(120.98±35.51)ng·mL~(-1);AUC_(0→72h)分别为(93.19±26.61),(179.46±52.86),(364.37±94.74)ng·mL~(-1)·h;AUC_(0→∞)分别为(96.70±27.42),(183.34±53.62),(372.86±95.84)ng·mL~(-1)·h;各剂量组的C_(max)、AuC_(0-72h)、AUC_(0→∞)随剂量的增加而成比例的增大,各组的K_(10)、t_(max)、t_(1/2β)、MRT_(0-72)、MRT_(0→∞)、CL/F、V/F等差异无统计意义.结论 口服给药剂量为1～4 mg时,匹伐他汀钙片在中国健康人体内具有线性药代动力学特征,其代谢特征基本与文献报道一致.     

Bioequivalence evaluation of norfloxacin 400 mg tablets (Uroxin and Noroxin) in healthy human volunteers

A bioequivalence study of two oral formulations of 400 mg norfloxacin was carried out in 18 healthy volunteers according to a single dose, two-sequence, cross-over randomized design at College of Pharmacy, King Saud University, Riyadh, Saudi Arabia, jointly with King Khalid University Hospital. The two formulations were: Uroxin (Julphar, United Arab Emirates) as test and Noroxin (Merck Sharpe & Dohme, BV, Netherlands). Both test and reference formulations were administered to each subject after an overnight fasting on 2 treatment days separated by 1 week wash-out period. After dosing, serial blood samples were collected for a period of 24 h. Plasma harvested from blood, was analysed for norfloxacin by a sensitive, reproducible and accurate HPLC method. Various pharmacokinetic parameters including AUC(0-t), AUC(0-infinity), C(max), T(max), T(1/2), and K(el) were determined from plasma concentrations for both the formulations and found to be in good agreement with reported values. AUC(0-t), AUC(0-infinity), and C(max) were tested for bioequivalence after log-transformation of data. No significant difference was found based on ANOVA; 90% confidence interval for test/reference ratio of these parameters were found within a bioequivalence acceptance range of 80-125%. Based on these statistical inferences, it was concluded that Uroxin is bioequivalent to Noroxin.     

Pharmacokinetics of hydroxy-3(S)-dihydroquinidine in healthy volunteers after intravenous and oral administration

The pharmacokinetics of hydroxy-3(S)-dihydroquinidine (HDHQ) were studied in 6 healthy volunteers following a 15 min intravenous infusion of a 300 or 400 mg dose, a 300 mg oral dose in solution and a 300 mg tablet administration on three separate occasions (random order) with at least one week intervals. Using a specific HPLC assay for HDHQ, the post-infusion and post-absorption plasma HDHQ concentrations declined bi-exponentially. Both oral forms of HDHQ were absorbed rapidly (tmax 1 h-1.2 h) with an absolute bioavailability of the oral solution (F = 0.54 to 0.93) which was not significantly different from that of the tablet (F = 0.66 to 0.90). HDHQ was rapidly and extensively distributed to the tissues with a high steady-state volume of distribution (6.82 +/- 1.85 l X kg-1). Mean elimination half-life was 6.7 +/- 1.4 h after IV infusion, 8.4 +/- 1.7 h after the oral solution and 11.3 +/- 4.4 h after the tablet administration. HDHQ was partially eliminated from the body in the unchanged non-conjugated form by the urine and renal clearance represented approximately 50% of the total body clearance. These results show that HDHQ is rapidly and almost completely absorbed and has potential for a twice daily administration regimen for the treatment of cardiac arrhythmias.