Pharmacokinetic profile and safety of BAY a 1040 GITS (gastrointestinal therapeutic system), a nifedipine once-a-day dosage form based on push-pull osmotic pump configuration, were investigated in Japanese healthy volunteers in single-dose and multiple-dose trials. The single dose trial was conducted in an open, randomized, 4-way crossover method, where 30 mg, and 40 mg nifedipine GITS tablets and 40 mg marketed nifedipine coat-core tablet (Adalat CR^®) were given after overnight fasting and 40 mg GITS was given with high-fat breakfast. The multiple-dose trial was an open, randomized, 2-way crossover trial using 40 mg GITS and 40 mg CR tablets for 7 days. In the plasma nifedipine concentration profile, C_max of 40 mg GITS was significantly lower than that of 40 mg CR, although AUC of 40 mg GITS was similar to that of 40 mg CR in the single-dose trial. When GITS was administered with high-fat breakfast, C_max was increased by 28%. In the multiple-dose trial, C_max of GITS was 43.2% lower than that of CR 40 mg, and C_min was 47.8% higher.
Results of both studies indicated that GITS has preferable controlled release properties in the once-a-day dosage form as well as Adalat CR. GITS showed lower intra-day fluctuation in the plasma concentration profile, compared to Adalat CR. However, no major difference was observed in the safety profile or blood pressure/pulse rate profiles between these two once-a-day dosage forms of nifedipine.

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Objectives: Tibolone (KB-889) is a novel compound that possesses tissue-specific hormonal effects. We investigated the pharmacokinetics of tibolone in postmenopausal women in four pharmacokinetic studies, namely a dose linearity study, a multiple dose study, a study in fasted condition, and a study in elderly. In this report, the results obtained from the above four studies are summarized.
Methods: In the dose linearity study, a single dose of 0.5 mg, 1 mg and 2 mg of tibolone was administered to 6 postmenopausal women using a 3-period crossover method with at least a 7-day wash-out period between treatments. In the multiple dose study, 2 mg of tibolone was administered once daily for 4 days to 6 postmenopausal women. In the study in fasted condition, a single dose of 2 mg of tibolone was administered to 6 postmenopausal women after overnight fasts. In the study in elderly, a single dose of 2 mg of tibolone was administered to 6 elderly women aged 65 or older. Plasma and urine concentrations of tibolone and its metabolites were measured.
Results and Conclusion: Plasma concentrations of the 3α-OH and 3β-OH metabolites of tibolone were measured, since the levels of tibolone and its Δ⁴-isomer were under or near the detection limits. After single dose administration of 0.5, 1 and 2 mg of tibolone, the means of C_max and AUC_0-12h of plasma 3α-OH metabolite were 2.3, 3.5 and 6.5 ng/mL and 10.2, 18.5 and 36.7 ng·Eh/mL, respectively, and those of 3β-OH metabolites were 0.9, 1.7 and 3.1 ng/mL and 4.6, 8.8 and 17.7 ng·Eh/mL, respectively. The means of T_max and T_{1/2 (6-12h)} of plasma 3α-OH and 3β-OH metabolites were between 3.7 and 5.7 h, and between 3.2 and 4.4 h, respectively. The pharmacokinetic properties of tibolone were considered to be linear within the dose range of 0.5 mg to 2 mg. In the multiple dose study, no accumulation was found. When comparing the pharmacokinetic parameters obtained from the study in fasted condition with those of day 1 of the multiple dose study, the absorption of tibolone was rapid under fasted condition, but AUC was not influenced by food intake. [The means of T_max of 3α-OH and 3β-OH metabolites were 1.17 and 1.33 h in fasted condition, and 3.83 and 4.00 h on day 1 of multiple dose.] Finally no difference in pharmacokinetics was found between postmenopausal women and elderly women in the comparison of the pharmacokinetic parameters obtained from the study in the elderly and those of day 1 of the multiple dose study.

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Cytochrome P4502C9 (CYP2C9) is a polymorphic enzyme which metabolizes a variety of medications. The CYP2C gene families are extensively homologous ; in particular, the nucleotide sequences in the areas adjacent to polymorphic sites are > 95% identical. Frequently, primers designed for amplification of CYP2C9 also amplify other CYP2C genes. Additional amplification of the other CYP2C alleles will thus yield an erroneous restriction pattern, resulting in misleading genotype of CYP2C9. Thus, a procedure to specifically amplify CYP2C9 alleles is necessary. In this study, a wax-mediated hot-start polymerase chain reaction (PCR) for the amplification of CYP2C9^* 1 and ^*3 alleles was tested. When serially diluted template DNA was amplified by the hot-start PCR followed by the agarose electrophoresis without the enzyme digestion, the 165 by band derived from CYP2C9 sequence was clearly detected without any non-specifically amplified band even from 10 ng DNA template, and the density of this band increased in proportion to the amount of template. On the other hand, when the PCR without the use of wax was performed, the amplification of the allele was irregular. This hot-start PCR gave a significant increase in the sensitivity for the detection of CYP2C9^* 1 and ^*3 alleles. The performance of the present method was studied with 64 Japanese volunteers. After the enzyme digestion of the products obtained by the wax-mediated hot-start PCR, only specific bands corresponding to CYP2C9^*1 and ^*3 alleles were obtained. This PCR method gave the consistent performance and low background. Thus, the wax-mediated hot-start PCR method should be useful in the genotyping of CYP2C9^*1 and ^*3, possibly including CYP2C9^*2 allele in the clinical laboratory.

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