Midazolam may be used as a probe drug for CYP3A activity to predict docetaxel clearances, hence reducing interindividual variability. Homozygotes for CYP3A5*3 and C3435T of MDR1 are common in our population, and their effects on pharmacokinetics of relevant substrates should be studied further.

Both nitric oxide (NO) and hydrogen sulfide (H(2)S) are two important gaseous mediators regulating heart function. The present study examined the interaction between these two biological gases and its role in the heart. We found that l-arginine, a substrate of NO synthase, decreased the amplitudes of myocyte contraction and electrically induced calcium transients. Sodium hydrogen sulfide (an H(2)S donor), which alone had minor effect, reversed the negative inotropic effects of l-arginine. The effect of l-arginine + sodium hydrogen sulfide was abolished by three thiols (l-cysteine, N-acetyl-cysteine, and glutathione), suggesting that the effect of H(2)S + NO is thiol sensitive. The stimulatory effect on heart contractility was also induced by GYY4137, a slow-releasing H(2)S donor, when used together with sodium nitroprusside, an NO-releasing donor. More importantly, enzymatic generation of H(2)S from recombinant cystathionine-γ-lyase protein also interacted with endogenous NO generated from l-arginine to stimulate heart contraction. In summary, our data suggest that endogenous NO may interact with H(2)S to produce a new biological mediator that produces positive inotropic effect. The crosstalk between H(2)S and NO also suggests an intriguing potential for the endogenous formation of a thiol-sensitive molecule, which may be of physiological significance in the heart.

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Polymorphisms in CBR3 may explain interindividual and interethnic variability of doxorubicin pharmacokinetics and pharmacodynamics.

Purpose: This tumor response pharmacodynamic model aims to describe primary lesion shrinkage in non^small cell lung cancer over time and determine if concentration-based exposure metrics for gemcitabine or that of its metabolites, 2 ¶,2 ¶-difluorodeoxyuridine or gemcitabine triphosphate, are better than gemcitabine dose for prediction of individual response. Experimental Design: Gemcitabine was given thrice weekly on days 1 and 8 in combination with carboplatin, which was given only on day 1of every cycle. Gemcitabine amount in the body and area under the concentration-time curves of plasma gemcitabine, 2 ¶,2 ¶-difluorodeoxyuridine, and intracellular gemcitabine triphosphate in white cells were compared to determine which best describes tumor shrinkage over time. Tumor growth kinetics were described using a Gompertzlike model. Results: The apparent half-life for the effect of gemcitabine was 7.67 weeks. The tumor turnover time constant was 21.8 weekÁcm. Baseline tumor size and gemcitabine amount in the body to attain 50% of tumor shrinkage were estimated to be 6.66 cm and 10,600 mg. There was no evidence of relapse during treatment. Conclusions: Concentration-based exposure metrics for gemcitabine and its metabolites were no better than gemcitabine amount in predicting tumor shrinkage in primary lung cancer lesions. Gemcitabine dose-based models did marginally better than treatment-based models that ignored doses of drug administered to patients. Modeling tumor shrinkage in primary lesions can be used to quantify individual sensitivity and response to antitumor effects of anticancer drugs.

The relationships between clozapine dosages, plasma concentrations, and clinical responses in Chinese schizophrenics were studied. Fourteen treatment-refractory schizophrenic patients were treated with clozapine for 12 weeks. Patients were assessed before and after 6 and 12 weeks of treatment using the Brief Psychiatric Rating Scale (BPRS), the Clinical Global Impression (CGI), and the Simpson-Angus Scale for Extrapyramidal Side Effect. Plasma clozapine concentrations were determined by high-performance liquid chromatography. Ten patients (71.4%) responded after 12 weeks of treatment. Although the mean daily dosage at week 12 (373 +/- 90 mg/day) was lower than that reported in American trials (444 mg/day), the mean plasma clozapine concentration attained (1,078 +/- 385 ng/ml) was higher. This higher concentration may be due to the lower body wight and the preponderance of women among our patients, absence of smoking and alcohol use, and/or ethnic difference between Chinese and non-Chinese. There was wide interindividual variation in the plasma clozapine concentrations. Compared with other studies, the plasma clozapine concentrations and the response rate were higher. Although the sample size was small, the findings are suggestive of pharmacokinetic and pharmacodynamic ethnic differences in Chinese with clozapine therapy.

Aims Aldo‐ketoreductases have been implicated in the metabolism of doxorubicin. We sought to assess the influence of AKR1C3 genetic variants on doxorubicin metabolism. Methods We sequenced AKR1C3 exon 5 and genotyped seven functional single nucleotide polymorphisms in CBR3, ABCB1 and SLC22A16 involved in doxorubicin pharmacology in 151 Asian breast cancer patients treated with doxorubicin‐containing chemotherapy, and correlated these genotypes with doxorubicin pharmacokinetics and pharmacodynamics. Results Two previously reported AKR1C3 intronic variants, IVS4–212 C>G and IVS4+218 G>A, were detected. The AKR1C3 IVS4–212 GG genotype was associated with significantly lower cycle 1 day 15 leucocyte (mean leucocytes 2.49 ± 1.57 × 109 vs. 3.85 ± 3.42 × 109 l−1, P = 0.007) and neutrophil counts (mean neutrophils 0.70 ± 1.01 × 109 vs. 1.56 ± 2.80 × 109 l−1, P = 0.008) and significant improvement of progression‐free survival [PFS, mean PFS 49.0 (95% confidence interval 42.2–55.8) vs. 31.0 (95% confidence interval 20.7–41.2) months, P = 0.017] and overall survival [OS; mean OS 64.4 (95% confidence interval 58.3–70.5) vs. 46.3 (95% confidence interval 35.1–57.5) months, P = 0.006] compared with those carrying at least one C allele. There was no significant association between AKR1C3 IVS4–212 C>G and doxorubicin pharmacokinetics. Of the other seven single nucleotide polymorphisms genotyped, CBR3 G11A correlated with doxorubicinol area under the concentration–time curve and OS, ABCB1 G2677T/A correlated with doxorubicin clearance and platelet toxicity, while ABCB1 IVS26+59 T>G correlated with OS. The AKR1C3 IVS4–212 C