Bantia S, Montgomery J A, Johnson H G, Walsh G M
BioCryst Pharmaceuticals, Inc., Birmingham, AL 35244, USA.
Immunopharmacology. 1996 Oct;35(1):53-63. doi: 10.1016/0162-3109(96)00123-3.
BCX-34 inhibits RBC PNP in vitro from humans, rats, and mice with IC50S ranging from 5 to 36 nM. BCX-34 also, in the presence but not in the absence of deoxyguanosine, inhibits human CCRF-CEM T-cell proliferation with an IC50 of 0.57 microM but not rat or mouse T-cell proliferation up to 30 microM. Inhibition of human T-cell proliferation is accompanied by an accumulation of intracellular dGTP with an associated reduction in GTP. These nucleotide changes do not occur in BC16A mouse T-cells and explain why proliferation is not inhibited by PNP inhibitors in this case. Reduction in intracellular GTP is not essential for the antiproliferative action of BCX-34. Oral bioavailability of BCX-34 in rats is 76%. BCX-34 is orally active in elevating plasma inosine in rats (2-fold at 30 mg/kg), in suppressing ex vivo RBC PNP activity in rats (98% at 3 h. 100 mg/kg), and in suppressing ex vivo skin PNP in mice (39% at 3 h, 100 mg/kg). The results demonstrate that BCX-34 inhibits human PNP and T-cell proliferation, is orally bioavailable in rodents, and pharmacologically active in vivo in rodents after oral dosing with no apparent side effects or toxicity. BCX-34 may, therefore, be useful in treating human T-cell proliferative inflammatory disorders.
BCX - 34在体外可抑制人、大鼠和小鼠的红细胞嘌呤核苷磷酸化酶（RBC PNP），其半数抑制浓度（IC50）范围为5至36 nM。在存在脱氧鸟苷但不存在脱氧鸟苷时，BCX - 34也可抑制人CCRF - CEM T细胞增殖，IC50为0.57 microM，但在高达30 microM时不抑制大鼠或小鼠T细胞增殖。人T细胞增殖的抑制伴随着细胞内dGTP的积累以及GTP的相应减少。这些核苷酸变化在BC16A小鼠T细胞中不会发生，这解释了在这种情况下PNP抑制剂为何不会抑制增殖。细胞内GTP的减少对于BCX - 34的抗增殖作用并非必不可少。BCX - 34在大鼠中的口服生物利用度为76%。BCX - 34口服具有活性，可提高大鼠血浆中的肌苷水平（30 mg/kg时提高2倍），抑制大鼠离体红细胞PNP活性（100 mg/kg时3小时抑制98%），并抑制小鼠离体皮肤PNP活性（100 mg/kg时3小时抑制39%）。结果表明，BCX - 34可抑制人PNP和T细胞增殖，在啮齿动物中具有口服生物利用度，口服给药后在啮齿动物体内具有药理活性，且无明显副作用或毒性。因此，BCX - 34可能对治疗人类T细胞增殖性炎症性疾病有用。
