Biomedical subjects

Li-Heng Pao

Publications and source records attributed to Li-Heng Pao.

3 recordsLinked to original sources

PubMed2004

In vitro and in vivo evaluation of the metabolism and pharmacokinetics of sebacoyl dinalbuphine.

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.

Analgesics, Opioid↗

PubMed2003

Novel inhibition of cis/trans retinoic acid interconversion in biological fluids--an accurate method for determination of trans and 13-cis retinoic acid in biological fluids.

All-trans retinoic acid (tRA, or tretinoin) can be metabolized through stereoisomerization to 13-cis retinoic acid (13-cRA) in vivo. We have developed a simple, sensitive and accurate method for analyzing tRA and 13-cRA in plasma with the addition of N-ethylmaleimide (NEM) and Vitamin C (Vit. C) to prevent the interconversion of cis/trans retinoic acid. All-trans RA, 9-cRA, and 13-cRA were well separated from each other in plasma by using a C18 precolumn and a column with a gradient solvent system of mobile phases A and B at a flow rate of 1.0 ml/min. In addition, thermal stability of tRA and cRA in plasma during the sample preparation under the temperature of 0 and 25 degrees C were studied. Our results showed that (1) the interconversion ratios (%) (cRA/tRA and tRA/cRA) were decreased with the addition of NEM and Vit. C and the minimum concentrations of NEM and Vit. C to inhibit the interconversion were 50 and 150 microM, respectively, (2) higher concentrations of NEM and Vit. C were required to prevent the interconversion at higher temperature, (3) the precision and accuracy of calibration curve with various concentration of tRA (1-1000 ng/ml) and 13-cRA (5-800 ng/ml) in plasma showed good linearity (r(2)=0.9992 and 0.9994), and between-day errors expressed by coefficient of variation (CV, %) for tRA and 13-cRA which were both less than 5.6%, (4) the mean recovery of the analytes were 78-94% for tRA and 80-92% for 13-cRA at concentration range from 1 to 1000 ng/ml and 5 to 800 ng/ml, respectively, and (5) the limit of quantitation of tRA and 13-cRA were 1 and 5 ng/ml, respectively. In addition, the HPLC method had been successfully applied to the tRA pharmacokinetic study in two hepatoma patients after receiving 45 mg/m(2) per day orally. Thus, our results suggest that the HPLC method for analyzing tRA and 13-cRA in plasma with the addition of NEM and Vit. C is a simple, sensitive and accurate method.

Carcinoma, Hepatocellular↗

PubMed2003

Single-point plasma or urine dextromethorphan method for determining CYP3A activity.

Dextromethorphan is used widely in vivo to phenotype the polymorphically expressed cytochrome P450 (CYP) 2D6. Also dextromethorphan is N-demethylated in vivo to 3-methoxymorphinan by human CYP3A4/5. The metabolic ratio (MR) of dextromethorphan/3-methoxymorphinan in plasma, saliva and urinary were examined as a possible in vivo probe of CYP3A activity. In limited previous studies, 4 h urinary samples were collected for determining the MR. To evaluate the repeatability and validity of previously reported and other potential phenotyping methods, the MR from urine samples (at various intervals), from plasma and from saliva (at varying time points) were determined 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 periods II and I, 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 periods I and II, respectively, with a 2 week washout period. Dextromethorphan and 3-methoxymorphinan are assayed by high-performance liquid chromatography. In the single-dose study, all of the urine MR revealed good repeatabilities for the periods (paired t-test). The urine MR at any time interval of 0-6 h, 0-8 h and 0-12 h correlated significantly with the MR from 0-24 h urine (r>0.8, p<0.05). In the multiple-dose study, all MR revealed good repeatabilities for the two periods (paired t-test). The plasma MR at any time between 0.5 h and 12 h, the saliva MR at 12 h and the urine MR at any interval between 0-2 h, 0-4 h, 0-6 h, 0-8 h, 0-12 h and 0-24 h could predict the MR from AUCtau(ss). In conclusion, the urine sample as 0-6 h, 0-8 h or 0-12 h in the single immediate-release dose (15 mg) or in the multiple controlled-release dose (60 mg) procedure, the saliva sample at 12 h, the urine sample at 0-2 h, 0-4 h, 0-6 h, 0-8 h, 0-12 h, 0-24 h or all plasma-sampling points 0.5-12 h could be used as the dextromethorphan MR for determining the CYP3A activity.

Administration, Oral↗