Drug-binding proteins in liver transplant patients.
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Biomedical subjects
Publications and source records attributed to M L Huang.
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A highly sensitive high-performance liquid chromatographic assay using amperometric detection has been developed for measuring alpha-tocopherol in plasma. Other minor components of vitamin E (beta-, gamma- and delta-tocopherols) can also be detected by this method. All-trans-retinol is simultaneously monitored by UV detection at 313 nm. This assay requires only 50 microliter of plasma for quantification of both vitamin E and A. The minimum detectable quantities for both alpha-tocopherol and retinol are 1.0 ng with corresponding signal-to-noise ratios of 4.0 and 3.5. The total chromatographic analysis time for each sample is less than 15 min. This assay has been used to determine the concentrations of vitamin A and E in plasma obtained from patients with liver disease, liver transplant patients and normal healthy volunteers.
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Early investigation of pharmacokinetic-pharmacodynamic relationships in Phase I/II may facilitate the further clinical development of a new drug. Although some pharmacology assessments in Phase I are often only surrogates for the therapeutic effect, PK-PD modelling of those effects provides in general crucial information on the drug's potency in vivo. A mathematical PK-PD expression allows explorative simulations on the rate of onset of drug action, on the intensity and duration of the effects for doses in future clinical trials, or in situations of altered drug kinetics. Furthermore, understanding of the PK-PD relationship early on in drug development may anticipate unnecessary exposure of human subjects to inappropriate drug doses or trials.
The absorption, metabolism, and excretion of the novel antipsychotic risperidone was studied in three healthy male subjects. One week after a single oral dose of 1 mg [14C]risperidone, 70% of the administered radioactivity was recovered in the urine and 14% in the feces. Unchanged risperidone was mainly excreted in the urine and accounted for 30, 11, and 4% of the administered dose in the poor, intermediate, and extensive metabolizer of debrisoquine, respectively. Alicyclic hydroxylation at the 9-position of the tetrahydro-4H-pyrido[1,2-a]-pyrimidin-4-one moiety was the main metabolic pathway. The active metabolite 9-hydroxy-risperidone accounted for 8, 22, and 32% of the administered dose in the urine of the poor, intermediate, and extensive metabolizer, respectively. Oxidative N-dealkylation at the piperidine nitrogen, whether or not in combination with the 9-hydroxylation, accounted for 10-13% of the dose. In methanolic extracts of feces, risperidone, and benzisoxazole-opened risperidone and hydroxylated metabolites were detected. 9-Hydroxy-risperidone was by far the main plasma metabolite. The sum of risperidone and 9-hydroxy-risperidone accounted for the largest part of the plasma radioactivity in the three subjects. Although the debrisoquine-type genetic polymorphism plays a distinct role in the metabolism of risperidone, the pharmacokinetics of the active fraction (i.e. risperidone plus 9-hydroxy-risperidone) remained similar among the three subjects.
The bioavailability of risperidone was evaluated in an open-label, randomized, two-way, crossover study comparing a 1-mg tablet with a 1-mg/ml oral solution. Both formulations were administered as a single 1-mg dose with a 10-day washout period between treatments. Of 26 healthy men who entered the study, 23 completed both treatment periods. Plasma concentrations of risperidone and the active moiety (risperidone plus its active metabolite, 9-hydroxyrisperidone) were determined by radioimmunoassays. For key pharmacokinetic values (Cmax, AUC), the 90% CIs on the relative bioequivalence of risperidone, 9-hydroxyrisperidone, and the active moiety were contained within the equivalence range of 80-120% (80-125% for log-transformed data). The results demonstrate that the 1-mg/ml oral solution and the 1-mg tablet are bioequivalent.
A 2-month-old female infant, presented with frequent choking and cyanosis during feeding, and poor sucking capability since the age of 45 days. Growth retardation with body weight and length below the third percentile, and head girth below the tenth percentile, were noted on admission. Generalized hypotonia, mild proximal muscle weakness and diminished tendon reflex were also noted. A biopsy from the left quadriceps femoralis showed uniform type 1 fiber (90%) predominance, and a decrease in fiber size and number of type 2 fibers. A biopsy from her father revealed uniform type 1 predominance (99.8%) and 30% central nuclei change. The course of her illness was rather short, and the patient has developed normally since the age of 4 months. Significant improvement in muscle strength and normal intelligence were observed after 3 years of clinical follow-up.