Quantitative rat liver function test by galactose single point method.

The purpose of this study was to investigate the galactose single point (GSP) method, a residual liver function test recently recommended by the US Food and Drug Administration, which can be a useful tool for rat liver function measurement. Rats were treated either with carbon tetrachloride (CCl(4)) alone (1 mL/kg, intraperitoneally [i.p.]) for one day or with isoniazid (INH) alone (150 mg/kg, i.p.) or (in order to ameliorate the effects of INH) with a combination of INH and bis-p-nitrophenyl phosphate (BNPP) (25 mg/kg, i.p.) for 21 days. Hepatotoxicity was assayed by plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities and scores of histological activity index-necroinflammation (HAI-NI) of the respective liver specimens. The GSP method in rats was defined by the galactose blood level after 60 min. Significant differences in GSP values were observed between controls and the CCl(4)-treated rats. After 21 days of treatment, no significant changes in AST and ALT values were observed among the control, INH and INH-BNPP groups. There were significant differences in average GSP values for controls (P < 0.001) and INH-BNPP (P < 0.001) compared with INH alone. Highly significant correlations (P < 0.001) were obtained between GSP and scores of HAI-NI for all the groups. GSP was concluded to be a more sensitive biomarker of INH-induced hepatotoxicity than AST or ALT in the rats. The GSP method has been proved to be a simple and useful tool for the quantitative determination of liver function in rats, which can possibly be extended to other animals.

Antinociceptive effect of a novel long-acting nalbuphine preparation.

BACKGROUND: A long-acting analgesic may be particularly desirable in patients suffering from long-lasting pain. The aim of the study was to evaluate the antinociceptive effect of a novel nalbuphine preparation and to determine its duration of action. METHODS: The antinociceptive effects of i.m. nalbuphine HCl in saline and nalbuphine base in sesame oil were evaluated in rats. The in vitro drug-releasing profiles of nalbuphine HCl and base in different preparations were also evaluated. RESULTS: We found that i.m. nalbuphine HCl 25, 50 and 100 micromol kg(-1) produced dose-related antinociceptive effects with a duration of action of 1.5, 2 and 3 h, respectively. i.m. nalbuphine base 100, 200 and 400 micromol kg(-1) also produced dose-related antinociceptive effects but with longer durations of action: 27, 49 and 55 h, respectively. In vitro studies demonstrated that nalbuphine base in sesame oil had the slowest drug-releasing profile of the different preparations. CONCLUSIONS: i.m. injection of an oil formulation of nalbuphine base produced a long-lasting antinociceptive effect.

Pharmacokinetics of sevoflurane uptake into the brain and body.

The aim of this study was to investigate the pharmacokinetics of sevoflurane uptake into the brain and body by comparing sevoflurane concentrations in internal jugular-bulb blood (Jsev), arterial blood (Asev) and pulmonary arterial blood (PAsev) over a fixed inspired sevoflurane concentration. Ten patients (aged 51-73 years), undergoing coronary artery bypass grafting surgery were enrolled in this study. They were anaesthetised using a constant 3.5% inspired sevoflurane concentration (CIsev) during the first hour of anaesthesia. During constant volume-controlled ventilation, we measured CIsev and end-tidal sevoflurane (CEsev) using infrared analysis. The sevoflurane concentration in the blood was analysed using gas chromatography, and cardiac output was measured using an Opti-Q pulmonary artery catheter. We found that it took 40 min for the brain concentration to equilibrate with arterial blood (Asev). Both CIsev-CEsev and Asev-PAsev gradients persisted during the study period. There was no further uptake of sevoflurane into the brain after 40 min; however, there was near-constant uptake into the body.

Antibiotic use in public hospitals in Taiwan after the implementation of National Health Insurance.

BACKGROUND AND PURPOSE: Only limited data is available on the patterns of antibiotic use in hospitals in Taiwan before and after the implementation of national health insurance. This study aimed to determine the patterns of use of antibiotics in public hospitals in Taiwan after the implementation of the National Health Insurance program and to compare these with patterns prior to the implementation. METHODS: Data on the annual use of all antibiotics in public hospitals in Taiwan during the period from fiscal year (FY) 1994-1995 to 1997-1998 were collected and analyzed. Hospitals included seven medical centers, 19 regional hospitals, 53 district hospitals, and eight specialty service hospitals. RESULTS: The annual cost of antibiotics made up 17.4% of the annual cost of all medication used in these hospitals in FY 1994-1995, and decreased year by year to 12.6% in FY 1997-1998. During the study period, 57.4% of the total cost of antibiotics were incurred by medical centers, 24.6% by regional hospitals, 16.2% by district hospitals, and 1.8% by specialty service hospitals. The most commonly used class of antibiotic was cephalosporins, accounting for 48.0% to 54.3% of total antibiotic costs. The second most commonly used class of antibiotic was penicillins, accounting for 15.9% to 17.4% of total antibiotic costs. In FY 1994-1995, the next most commonly used classes of antibiotics were aminoglycosides, fluoroquinolones, and other beta-lactams, respectively, but by FY 1997-1998 these had changed to fluoroquinolones, glycopeptides, and aminoglycosides, respectively. Among the various cephalosporins used, first-generation cephalosporins accounted for 76.1% of all cephalosporins used in FY 1994-1995, which increased year by year to 84.0% in FY 1997-1998. Second-generation cephalosporins accounted for 20.7% of all cephalosporins used in FY 1994-1995, decreasing to 13.2% in FY 1997-1998. CONCLUSION: The introduction of the National Health Insurance program in Taiwan brought about a major change in antibiotic use patterns in public hospitals.

Transdermal delivery of nalbuphine and nalbuphine pivalate from hydrogels by passive diffusion and iontophoresis.

The objective of this study was to evaluate the in vitro transdermal permeation of nalbuphine hydrochloride (CAS 23277-43-2) (NA) and nalbuphine pivalate (NAP), a novel prodrug of NA, from different hydrogel formulations under passive diffusion as well as iontophoresis. Various concentrations of polymers, including polyvinylpyrrolidone (PVP) and hydroxypropyl cellulose (HPC) were used in the hydrogel formulations. The passive permeation rate of NA was affected by the polymer concentrations, which can be attributed to different viscosities of the hydrated formulations; whereas the passive permeation rate of NAP was not influenced by the various polymer concentrations. Iontophoresis significantly increased the permeation rates of NA and NAP from various hydrogel formulations through skin; the enhancement ratios were higher for NA in all the formulations studied. The iontophoretic permeation rates of NA were slightly decreased by the incorporation of polymers; however, the transdermal flux and membrane potential were independent of polymer concentrations for both NA and NAP, demonstrating that the polymer concentrations in the hydrogel formulations did not have significant effects on the iontophoretic permeation of NA and NAP.

High-performance liquid chromatographic method for the simultaneous determination of nalbuphine and its prodrug, sebacoyl dinalbuphine ester, in dog plasma and application to pharmacokinetic studies in dogs.

For the determination of nalbuphine and its long acting prodrug, sebacoyl dinalbuphine ester (SDN), in biological samples, a reversed-phase high-performance liquid chromatographic method using dual detectors was established. Ultraviolet and fluorescence detectors were connected in series for determining SDN and nalbuphine, respectively. The two analytes and internal standard were extracted from plasma by alkaline liquid-liquid extraction using n-hexane-isoamyl alcohol (9:1, v/v). The calibration curve for nalbuphine was linear over the range from 10 to 2,500 ng/ml, while the range was 25 to 2,500 ng/ml for SDN. The within- and between-day precision and accuracy were all within 10% for both nalbuphine and SDN over these concentrations. The method was applied successfully to a pharmacokinetic study of SDN administered at 20 mg/kg to two beagle dogs. Pharmacokinetic analysis revealed that SDN followed a linear one-compartment model with an elimination half-life of 74.7 min. Formation of nalbuphine after intravenous administration of SDN was observed in the first time point sample (5 min). These results indicate that SDN is rapidly metabolized to its active moiety, nalbuphine, in dogs and no other metabolites are detected in plasma.

Delivery of nalbuphine and its prodrugs across skin by passive diffusion and iontophoresis.

The in vitro transport of nalbuphine (NA) and its prodrugs across various skins was investigated in order to assess the effects of prodrug lipophilicity on passive as well as iontophoretic permeation. The passive diffusion of NA and its prodrugs increased with the drug lipophilicity. Iontophoresis significantly increased the transport of NA and its prodrugs; the enhancement ratio was highest for NA and decreased as the drug lipophilicity increased. Measurements using intact and stratum corneum (SC)-stripped skins showed that the SC was the major skin diffusion barrier for the passive permeation of NA and nalbuphine pivalate (NAP). The iontophoretic permeation of NA and NAP across intact and SC-stripped skins indicated that the SC layer was not rate-limiting for the permeation of NA, but remained the rate-limiting barrier for transdermal permeation of NAP. Permeation studies using SC-stripped and delipidized skins suggested that the intercellular pathway was the predominant route for the passive permeation of NA and NAP as well as the iontophoretic permeation of NAP across the SC. The relative rates of passive and iontophoretic permeation across Wistar rat skins demonstrated that a significant amount of NA may permeate skin via the appendageal routes, whereas NAP permeated predominantly through the lipid matrix.

Does Chinese ethnicity affect the pharmacokinetics and pharmacodynamics of angiotensin-converting enzyme inhibitors?

Information from clinical and pharmacokinetic studies of angiotensin-converting enzyme inhibitors (ACEIs) has come from subjects who are mostly male and Caucasian, but the use of ACEIs extends to populations worldwide. Significant differences between Chinese in general and male Caucasians have been demonstrated in the pharmacokinetics/dynamics of other drug classes that could have implications for the use of ACEIs in the Chinese population. These include: significant Chinese/Caucasian genetic variation in the renin-angiotensin system based on an insertion/deletion (O/D) polymorphism of the ACE gene; the genetic determination of plasma ACE activity in the Chinese population; and genetic factors involving the disease substrate which may also influence the response to treatment. Oral and IV pharmacokinetic data from various studies of Chinese and Caucasian subjects are available for cilazapril, fosinopril, and perindopril, and pharmacodynamic data are available for eight different ACEIs. Based on these data, there are few differences among the pharmacokinetics of ACEIs between Chinese and Caucasians. Most ACEIs showed good blood pressure lowering efficacy in Chinese (benazepril, enalapril, fosinopril and spirapril), with perhaps less blood pressure lowering with cilazapril or a relatively shorter-term effect with cilazapril or perindopril compared to Caucasions. Chinese experience more cough from ACEIs (captopril and enalapril) than Caucasians. Data suggest that fosinopril may not induce cough in as many subjects as other ACEIs, and this seems to be true of Chinese as well. The mechanism, currently unknown, could involve fosinopril's dual elimination pathway (hepatic and renal). Pharmacokinetic data also support the use of fosinopril in congestive heart failure where elimination pathways may be impaired. In conclusion, ethnic differences between Chinese and Caucasians with respect to ACE and AGT gene polymorphism, which might be expected to differentially affect the action of ACEIs in these two ethnic groups, do not, in fact, have such an effect. Rather, differences among the ACEIs appear to be more important. Journal of Human Hypertension (2000) 14, 163-170.

Cardiovascular effect and simultaneous pharmacokinetic and pharmacodynamic modeling of pimobendan in healthy normal subjects.

Pimobendan is a new inotropic agent with vasodilator properties. We have reported the pharmacokinetics of enantiomers of pimobendan in healthy humans. The present report focuses on the pharmacodynamic effect of pimobendan and a simultaneous pharmacokinetic-pharmacodynamic modeling. Eight normal healthy volunteers were studied with oral administration of 7.5 mg and i.v. administration of 5 mg of racemic pimobendan. Concentrations of enantiomers of pimobendan were determined by high performance liquid chromatography. Cardiovascular effects of pimobendan were evaluated by echocardiography. Oral pimobendan significantly reduced 29.0% and 16.5% of the left ventricle end-systolic dimension (LVESD) and end-diastolic dimension, respectively. The mean velocity of circumferential fiber shortening, ejection fraction, and fractional shortening significantly increased 105.9%, 29.8%, and 46% from their baseline values, respectively. The cardiovascular effects of i.v. pimobendan were similar but to a lesser extent. Plots of effect versus plasma concentration (Cp) showed counterclockwise hysteresis loops. A hypothetical effect compartment was established and incorporated into a sigmoid Emax model to describe the time courses of Cps of pimobendan and effects on LVESD. The maximal changes (Emax) in LVESD would be 2.60 +/- 0.51 cm and 2.30 +/- 0.13 cm as estimated from plasma data of (+)- and (-)-pimobendan, respectively. The estimated effect-site concentrations corresponding with 50% of the maximal effect (Ce50) were 6.54 +/- 1.35 and 6.64 +/- 1.35 ng/ml for (+)- and (-)-pimobendan, respectively. A simultaneous pharmacokinetic-pharmacodynamic model could be established to suppress the hysteresis loop and to predict the pharmacological effect based on Cp.

Mucoadhesive buccal disks for novel nalbuphine prodrug controlled delivery: effect of formulation variables on drug release and mucoadhesive performance.

The objective of this work was to assess the effects of drug solubility and loading percent, as well as Carbopol 934/hydroxypropylcellulose (CP/HPC) ratio, on drug release and mucoadhesive performance of the nalbuphine prodrug loaded buccal disks. Drug release rates for the disks were found to be a function of drug solubility, with higher drug release rates for disks loaded with more hydrophilic prodrugs and an increased amount of beta-cyclodextrin. The drug release rates increased with loading percents for nalbuphine hydrochloride, whereas an opposite drug release trend was observed for disks loaded with nalbuphine enanthate, which can be explained by the diffusional drug release mechanism. The CP/HPC ratio affected release rates of nalbuphine enanthate, whereas the ratio had no impact on the release of nalbuphine hydrochloride. Within the 2 days of experiment time, all formulations attached well to the porcine buccal tissues, indicating those formulation variables had no influence on the mucoadhesive performance of CP/HPC-based buccal disks.

Fosinopril: pharmacokinetics and pharmacodynamics in Chinese subjects.

This study examined thepharmacokinetics and pharmacodynamics of fosinopril (IVand oral) in Chinese subjects to determine whether they were different from a group of somewhat heavier and older Western control subjects previously published using the same methods. It was an open-label, randomized, balanced, two-way crossover study comparing oral and IV pharmacokinetics in 12 healthy Chinese subjects in a clinic in Taiwan. Each subject received 10 mg of oral fosinopril or 7.5 mg of IV fosinoprilatin a randomized sequence with sampling for fosinoprilat concentrations over 48 hours. Standard pharmacokinetics, including AUC, Cmax Tmax, T 1/2, Vss, bioavailability, total clearance, and renal and nonrenal clearance, were determined as well as pharmacodynamic effects on angiotensin-converting enzyme (ACE) activity. Following oral administration of 10 mg fosinopril, AUC0-T and AUCinf were 1,556 +/- 586 ng x hr/mL and 1,636 +/- 620 ng x hr/mL, respectively; T 1/2 was 17.4 +/- 11.4 hr; Cmax was 183.4 +/- 59.4 ng/mL; and median Tmax was 4.0 hr, with > 99% protein binding. Following IV administration of 7.5 mg fosinoprilat, AUC0-T and AUCinf were 7,727 +/- 2,638 ng x hr/mL and 7,816 +/- 2,693 ng x hr/mL, respectively; T 1/2 was 13.0 +/- 5.2 hr; and median Tmax was 4.0 hr, with 99.5% +/- 0.22% protein binding and a Vss of 5,850 +/- 2,780 mL. Bioavailability was 22.3% +/- 7.9%. Percent urinary excretion was 7.6% +/- 2.6% after oral dosing and 42.6% +/- 6.1% after IV dosing. After IV, dosing total clearance was 1,088 +/- 439 mL/hr, renal clearance was 472 +/- 213 mL/hr, and nonrenal clearance was 617 +/- 246 mL/hr. ACE inhibition was essentially complete through 12 hours and markedly reduced through 24 hours. Compared to a somewhat heavier and older previously reported control group, pharmacokinetic values were similar except for a slightly lower AUC and total clearance in Chinese and a statistically significantly lower nonrenal clearance. Pharmacodynamic effects on ACE activity were essentially identical. There is no reason to expect significant differences in fosinopril dosing or effect in a Chinese population compared to a Western population.

Comparison of PCA nalbuphine and morphine in Chinese gynecologic patients.

BACKGROUND: The aim of this study was to evaluate the efficacy and side effects of PCA nalbuphine (intravenous) versus morphine on postoperative pain in Chinese gynecologic patients. METHODS: Sixty women undergoing abdominal hysterectomy or myomectomy under spinal anesthesia were enrolled into the investigation. Patients were randomly divided into 2 groups (n = 30 each). Group 1 received intravenous nalbuphine using PCA device for the management of postoperative pain, whereas group 2 received PCA morphine for the same purpose. During the first 48 hours postoperatively, we collected the following data: analgesic doses, pain scores, vital signs, nausea, vomiting, pruritus and dizziness. RESULTS: The results showed that despite different treatments, pain scores on day 1 and day 2 postoperatively were low and were not significantly different between groups. Meanwhile, the cumulative consumption of PCA nalbuphine (32 +/- 10 mg) and PCA morphine (30 +/- 9 mg) was similar. Both treatments showed only minor side effects and the incidence of each side effect was not significant between groups. CONCLUSIONS: Both PCA nalbuphine and morphine are effective in the treatment of postoperative pain in Chinese gynecologic patients undergoing hysterectomy or myomectomy after spinal anesthesia and the potency of nalbuphine is similar to that of morphine.

Determination of morphine by high-performance liquid chromatography with electrochemical detection: application to human and rabbit pharmacokinetic studies.

A rapid, sensitive, precise and accurate high-performance liquid chromatographic assay with coulometric electrochemical detection was developed for the determination of morphine in human, rabbit, pig and dog plasma. It includes a one-step extraction procedure with hexane-isoamyl alcohol (1:1, v/v) at pH 8.9 (adjusted with phosphoric acid) and reversed-phase liquid chromatography on a microPorasil column. The mobile phase was composed of 5 mM sodium acetate buffer (pH 3.75)-acetonitrile (25:75, v/v). A flow-rate of 1.2 ml/min at 20 degrees C was used. The working potentials for the electrochemical detector were +0.20 V for detector cell 1, +0.55 V for detector cell 2 and +0.75 V for the guard cell. The limit of detection of morphine was 100 pg/ml of plasma. Repeatability, precision and accuracy were also determined concomitantly. The calibration graphs were linear in the concentration range 0.25-250 ng/ml with correlation coefficients of 0.998+/-0.01 and with a minimum intercept of 0.05+/-0.08. The precision in plasma was acceptable, with coefficients of variation less than 11%. The absolute recoveries of morphine and nalbuphine (internal standard) were between 86 and 89% and independent of morphine concentration. Pharmacokinetics after oral morphine [MST Continus (morphine sulphate tablets) 30 mg, Bard Pharmaceutical, Cambridge, UK] in humans revealed a one-compartment first-order absorption model with one absorption phase and one elimination phase. The absorption and elimination half-lives were 2.46 and 1.80 h, respectively. Pharmacokinetics after intravenous morphine (3 mg/kg) in rabbits showed a linear two-compartment open model with one distribution phase and one elimination phase. The distribution and elimination half-lives were 0.5 and 33.8 h, respectively.

Phase II and pharmacokinetic study of paclitaxel therapy for unresectable hepatocellular carcinoma patients.

Hepatocellular carcinoma (HCC) is a common lethal disease in Asia and there is no effective chemotherapy. Identification of new effective drugs in the treatment of inoperable HCC is urgently need. This is a phase II clinical study to investigate the efficacy, toxicity and pharmacokinetics of paclitaxel in HCC patients. Twenty patients with measurable, unresectable HCC, normal serum bilirubin, normal bone marrow and renal functions were studied. Paclitaxel 175 mg m(-2) was given intravenously over 3 h every 3 weeks. No complete or partial responses were observed. Five patients had stable disease. Major treatment toxicities (grade 3-4) were neutropenia (25%), thrombocytopenia (15%), infection (10%) and allergy (10%). Treatment-related deaths occurred in two patients. The median survival was 12 weeks (range 1-36). Paclitaxel is metabolized by the liver and the pharmacokinetics of paclitaxel in cancer patients with liver involvement or impairment may be important clinically. Pharmacokinetic study was completed in 13 HCC patients. The paclitaxel area under the curve was significantly increased (P < 0.02), clearance decreased (P < 0.02) and treatment-related deaths increased (P = 0.03) in patients with hepatic impairment. In conclusion, paclitaxel in this dose and schedule has no significant anti-cancer effect in HCC patients. Paclitaxel should be used with caution in cancer patients with liver impairment.

Novel single-point plasma or saliva dextromethorphan method for determining CYP2D6 activity.

O-Demethylation of dextromethorphan co-segregates with 4-hydroxylation of debrisoquin and is used for CYP2D6 phenotyping. In most previous studies, 8-h urinary samples were collected for determining the dextromethorphan metabolic ratio (dextromethorphan/dextrorphan molar ratio). In addition, a salivary sampling at 3 h had been suggested for the phenotyping. To evaluate the repeatability and validity of previously reported and other potential phenotyping methods, we determined the metabolic ratios from urine samples (for various intervals), or from plasma or saliva (at varying time points) after repetitive single doses of immediate-release or repetitive multiple doses of controlled-release dextromethorphan preparations. For the single-dose study, each of 12 subjects received 15 mg of immediate-release dextromethorphan in period I and period II, respectively, with a 1-week washout period. For the multiple-dose study, each of 16 subjects received 60 mg controlled-release dextromethorphan twice daily for 5 days in period I and period II, respectively, with a 2-week washout period. Dextromethorphan and dextrorphan were assayed by high-performance liquid chromatography. In the single-dose study, most metabolic ratios revealed good repeatabilities for the two periods (paired t test). The metabolic ratio from urine collected for 4 h, 6 h, 8 h or 12 h from plasma at any time between 1 h and 5 h or at 8 h, or from saliva at 2 h or 6 h, could reflect that from 0- to 24-h urine or AUCinfinity. In the multiple-dose study, all metabolic ratios revealed good repeatabilities. The plasma metabolic ratio at any time between 0.5 h and 10 h or the saliva metabolic ratio at any time between 3 h and 12 h, but not the urine metabolic ratio from any interval, could predict the metabolic ratio from ACUSStau. The 2 h, 3 h, 4 h or 5 h plasma metabolic ratio and 6 h saliva metabolic ratios after a single dose correlated significantly with their corresponding multiple-dose metabolic ratio (r > 0.8, P < .05). In conclusion, the plasma sample at 2 h, 3 h, 4 h or 5 h or the saliva sample at 6 h in either the single immediate-release (15 mg) or the multiple controlled-release dose (60 mg) procedure could be used for determining the dextromethorphan metabolic ratio.

Single dose pharmacokinetic study of lithium in Taiwanese/Chinese bipolar patients.

OBJECTIVE: The purpose of this study is to investigate the single dose pharmacokinetics of lithium in Taiwanese/Chinese bipolar patients for future interracial comparisons. METHOD: Eight bipolar patients took 900 mg of lithium carbonate after overnight fasting. Blood samples of 5 mL were taken after 15 min, 30 min, 45 min, 1 h, 2 h, 3 h, 4 h, 7 h, 9 h, 15 h, 25 h and 31 h after dosing. The computer programs CSTRIP and PCNONLIN were used for pharmacokinetic analysis. RESULTS: The pharmacokinetic parameters obtained were as follows: Cmax, 0.970 +/- 0.170 (SD) mmol/L; Tmax, 1.59 +/- 0.78 h; AUC31 h = 548.9 +/- 135.4 mmol x m/L; AUC to infinity = 722.6 +/- 262.7 mmol x m/L; beta-half-life = 16.3 +/- 7.18 h; kappa-half-life = 0.613 +/- 0.442 h; Cl(oral) = 1.13 +/- 0.39 mL/min/kg; Vd/F = 1.43 +/- 0.387 L/kg. Most of the pharmacokinetic parameters were within the ranges reported in investigations of Caucasian subjects. CONCLUSIONS: This study showed that racial differences in lithium pharmacokinetics might not exist. We suggest that methodological designs, including method of blood sampling, measurement of lithium, and pharmacokinetic and statistical calculations, be standardised if future cross-ethnic comparisons are to be conducted.

Dose-dependent reduced haloperidol/haloperidol ratios: influence of patient-related variables.

Plasma reduced haloperidol (RH) concentrations or RH to haloperidol (HL) ratios have been suggested to be important in determining the clinical efficacy and extrapyramidal side effects of HL. In this study, we measured the steady-state plasma HL and RH levels by high performance liquid chromatography and analyzed the effects of various variables (dose, gender, age, and body weight) on RH/HL ratios in four dose groups of Chinese schizophrenic inpatients: 10 mg/day (n = 84), 20 (n = 111), 30 (n = 29), and 60 (n = 55). In addition, the polymorphic distribution of RH/HL ratios, suggested by previous investigators, was further tested in each dosage group (for controlling the potential dosage effect on RH/HL ratios). As a result, both age and body weight could influence RH/HL ratios. Each year increase in age (after adjusting the effects of gender, body weight, and dosage) would elevate the RH/HL ratio by 0.0067 (P < 0.0001). On the other hand, after adjusting gender, age, and dosage effects, each kg increment in body weight would decrease the RH/HL ratio by 0.0044 (P < 0.01). Gender did not influence the ratio. Furthermore, the high dosage groups had higher RH/HL ratios (even with other variables being controlled). In comparison with the 10 mg group, the 60 mg group exhibited a higher mean RH/HL ratio by 0.84 (P < 0.0001) and the 30 mg group did by 0.31 (P < 0.0001). The 20 mg group was almost equal to the 10 mg group in RH/HL ratios. Besides, at each dosage group, the frequency distribution of RH/HL ratios seemed to be predominantly unimodal with a small proportion of extreme outliers. The results of this study clearly indicate that aging or a high dose (> or = 30 mg/day) of HL could raise the plasma RH/HL ratio, while an increasing body weight would reduce that. In contrast, gender does not affect the ratios.

Dextromethorphan phenotyping and haloperidol disposition in schizophrenic patients.

This study examined the relationship between the metabolic ratios of dextromethorphan/dextrorphan, haloperidol disposition, and the incidence of extrapyramidal side effects in schizophrenic patients. Eighteen schizophrenic patients were phenotyped with a test dose of dextromethorphan prior to the initiation of haloperidol treatment. The metabolic ratio of dextromethorphan/dextrorphan was determined in each patient. Patients were treated with oral haloperidol 10 mg/day for 2 weeks. Blood samples for haloperidol and reduced haloperidol were obtained at week 2 of haloperidol treatment. Haloperidol and reduced haloperidol plasma concentrations were assayed by HPLC with electrochemical detection. Significant correlations of dextromethorphan/dextrorphan metabolic ratios vs. plasma haloperidol concentrations, reduced haloperidol concentrations, and reduced haloperidol/haloperidol ratios were found (r = 0.726, P = 0.0007; r = 0.782, P = 0.0001; and r = 0.619, P = 0.006, respectively). Ten patients who experienced extrapyramidal side effects had higher reduced haloperidol concentrations and reduced haloperidol/haloperidol ratios than the other patients (2.49 +/- 1.42 [S.D.] ng/ml vs. 1.10 +/- 0.46 ng/ml, P = 0.014 and 0.287 +/- 0.102 vs. 0.192 +/- 0.065, P = 0.030). The former also had a trend to have higher haloperidol concentrations and dextromethorphan/dextrorphan ratios than the latter (8.04 +/- 2.91 ng/ml vs. 5.83 +/- 1.79 ng/ml, P = 0.066 and 0.023 +/- 0.017 vs. 0.011 +/- 0.010, P = 0.077). Phenotyping patients has the potential to assist clinicians in predicting plasma drug concentrations during the subsequent neuroleptic drug treatment. Further research with phenotyping and psychotropic drug metabolism in psychiatric patients is needed.

Blood levels of reduced haloperidol versus clinical efficacy and extrapyramidal side effects of haloperidol.

1. The studies of relationships between blood levels of reduced haloperidol HL (RH) and clinical efficacy in haloperidol (HL)-treated patients have yielded variable results. On the other hand, the contribution of RH upon HL's extrapyramidal side effects (EPS) had been suggested in animal models as well as in preliminary clinical studies with limited subjects. 2. This study explored the relationships between blood drug levels and clinical effects and EPS of HL in 48 Chinese acutely exacerbated schizophrenic inpatients. After a single-blind placebo period of one week, the patients were treated with a fixed dose 10 mg of HL for two weeks. Steady-state levels of HL and RH in plasma (n = 48) and in red blood cells (RBC) (n = 37) were measured by high performance liquid chromatography. 3. The mean RH/HL ratio in RBC in the Chinese (0.55) is lower than that in non-Chinese patients as reported in the literature (> 2), so is the RH/HL ratios in plasma. 4. No significant relationship emerged between percent improvement in BPRS total score and any of drug indices (HL, RH, sum of two compounds (HL+RH), and RH/HL ratio) in plasma and in RBC. Furthermore, the responders did not differ significantly from the nonresponders in each drug index. 5. Plasma RH levels were significantly higher in 30 patients experiencing EPS compared with the other 18 patients (mean 2.14 +/- 1.71 (S.D.) ng/ml vs. 1.38 +/- 0.37 ng/ml, p < 0.05). No significant differences in other drug indices were noted between subjects with or without EPS.

Pharmacokinetics of fosinoprilat in Chinese and whites after intravenous administration.

The pharmacokinetics of fosinoprilat was studied in 12 healthy Chinese men after a 7.5 mg intravenous dose of fosinoprilat. The data were compared with those from an earlier study using the same protocol in nine healthy white men. Blood and urine samples were obtained before and at various time intervals after fosinoprilat administration up to 24 hours and 48 hours, respectively. Pharmacokinetic parameters were calculated by fitting the plasma or serum concentrations to a three-compartment model. The total clearance (Clt), renal clearance (ClT), and nonrenal clearance (ClNR) were significantly lower in Chinese (16.29 +/- 6.92, 6.85 +/- 2.97, and 9.44 +/- 5.08 mL.hr-1.kg-1) than those obtained in whites (29.88 +/- 6.36, 13.55 +/- 3.45, and 16.33 +/- 5.07 mL.hr-1.kg-1). The Chinese subjects had a significantly lower volume of distribution (Vc [volume of distribution of central compartment] and Vdss [volume of distribution at steady state]) (29.38 +/- 21.12 and 73.67 +/- 40.20 mL/kg) than white men (58.14 +/- 15.01 and 152.49 +/- 24.89 mL/kg). The Chinese men also had a shorter elimination half-life than whites, although not statistically significant. The respective half-lives in Chinese and whites were 5.51 +/- 1.53 and 8.24 +/- 1.99 hours. The significant differences in ClNR and ClR may be related to lower liver elimination function and lower kidney excretory function, respectively. Plasma protein binding may contribute to part of the difference in the volume of distribution. Chinese men have smaller volume of distribution and clearances of fosinoprilat after intravenous administration compared with white men. The cumulative urine excretion of fosinoprilat was not different between Chinese and whites. Chinese may require a lower fosinoprilat dosage to obtain plasma concentrations similar to whites after intravenous administration. However, since a relatively high variation was found in fosinopril oral absorption, the oral dosage of fosinopril for Chinese and whites may not be different. Further study is obviously needed to elucidate whether the pharmacodynamic effect may be different between Chinese and whites.