The present study demonstrated that the three genotypes according to rs1495741 were in good accordance with conventional NAT2 alleles-inferred phenotypes and the tag SNP could be used as a proxy to determine the susceptibility to ATDIH.

No abstract

SummaryThe 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.

Tween-PEG successfully improved oral NAL bioavailability and could formulate a useful oral dosage form for patient's convenience.

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ABSTRACT:A diester prodrug of nalbuphine, sebacoyl dinalbuphine (SDN), and its long-acting formulation are currently being developed to prolong the duration of nalbuphine. A comparative in vitro hydrolysis study was conducted for SDN in rat, rabbit, dog, and human blood. Both SDN and nalbuphine in blood or plasma were measured by high-performance liquid chromatography. The hydrolysis rates of SDN in blood were ranked as follows: rat > rabbit > human > dog. The rapid formation of nalbuphine in the blood accounted for almost 100% of the prodrug, which supported the contention that nalbuphine is the major metabolite after SDN hydrolysis. The hydrolysis profiles of SDN were similar both in plasma and in red blood cells when compared in the blood. In vitro release results of SDN long-acting formulation showed that the rate-limited step of SDN hydrolysis to nalbuphine in blood is the penetration of SDN from oil into the blood. After intravenous administration of SDN in sesame oil into rats, nalbuphine quickly appeared in plasma and, thereafter, exhibited monoexponential decay. Pharmaceutical dosage forms affecting the drug disposition kinetics were demonstrated after intravenous administration. The AUC of nalbuphine was significantly higher and clearance was significantly lower, without changes in the t 1/2 of nalbuphine after intravenous dosing of SDN in sesame oil when compared with that of intravenous dosing with nalbuphine HCl in rats. Overall, these results suggest that SDN fulfilled the original pro-soft drug design in which the prodrug can rapidly metabolize to nalbuphine, and no other unexpected compounds were apparent in the blood.Esters have been the most common approach for prodrug development, because ester linkage of prodrugs tends to be converted efficiently to the active species through wide variability of esterase in the organs and tissues (Williams, 1985;Leinweber, 1987). The ester prodrugs apparently show that the safety and pharmacological actions of prodrugs seem to be the same as those for the parent compound (He et al., 1999;Ishikawa, 1999;Noble and Goa, 1999;Doucette and Aoki, 2001;Beaumont et al., 2003;Fischer et al., 2003). Nalbuphine is a potent -receptor agonist, -receptor antagonist analgesic with relatively low side effects (Jasinski and Mansky, 1972;Beaver and Feise, 1978). However, its short elimination half-life results in frequent injections for control of moderate to severe pain in clinical cases (Lo et al., 1987). SDN is a novel synthetic diester prodrug of nalbuphine designed to have high lipophilicity that consequently prolongs the duration of nalbuphine after intramuscular injection (Fig. 1).A successfully designed prodrug should not only be well absorbed, but should also metabolize primarily and readily to its active moiety. The prodrug should fulfill several criteria as proposed by Bodor (1984). Basically, no unexpected compound should be formed in vivo. Red blood cells and plasma are known to contain esterase (Leinweber, 1987;Cossum, 1988). In this study, SDN was examined for i...

A novel sensitive and selective liquid chromatography-tandem mass spectrometry (LC-MS-MS) method simultaneously determined buprenorphine (BUP) and its active metabolite, norbuprenorphine (NBUP), and a coformulant, naloxone was developed, validated and applied successfully in humans. Buprenorphine-d 4 and norbuprenorphine-d 3 were used as the internal standard. The analysis was performed on a silica column, and the mobile phase was isocratic and composed of acetonitrile:2 mM ammonium formate in H2O (82:18, v/v). Mass spectrometry employed multiple reaction monitoring modes with transitions of m/z 468.1-55.2 for BUP, 414.2-101.2 for NBUP, 328.3-310.3 for naloxone, 472.1-59.2 for buprenorphine-d 4 and 417.2-101.2 for norbuprenorphine-d 3 . Lower limit of quantification (LLOQ) of the analytical method was 0.05 ng mL -1 for BUP, 0.1 ng mL -1 for NBUP and 0.025 ng mL -1 for naloxone, respectively. The standard calibration curves of BUP, NBUP and naloxone were linear over the concentration range of 0.05-20 ng mL -1 , 0.1-20 ng mL -1 and 0.025-20 ng mL -1 , respectively. The precisions (RSD) and accuracies (RE) of LLOQ and other QC samples were in acceptable range, with RSD \ 20% and RE ± 20% for LLOQ and RSD \ 15% and RE within ±15% for QC samples. The method was accurate, precise and specific, and was applied to the pharmacokinetic study of buprenorphine in healthy volunteers.

Mannitol, an FDA-approved excipient, was found to be a CYP2E1 inhibitor. Mannitol may be a useful adjuvant for drugs that induce hepatotoxicity through CYP2E1, such as INH and RIF.