The effect of increasing gastric pH upon the bioavailability of orally-administered foscarnet.
The effect of increasing gastric pH upon the bioavailability of orally-administered foscarnet.
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增加胃 pH 值对口服膦甲酸生物利用度的影响。
DOI：
10.1016/s0166-3542(98)00024-2
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发表时间：
1998
影响因子：
7.6
通讯作者：
Kornhauser,DM
中科院分区：
文献类型：
--
作者：
Barditch-Crovo,PA;Petty,BG;Gambertoglio,J;Nerhood,LJ;Kuwahara,S;Hafner,R;Lietman,PS;Kornhauser,DM
对于全身用药，抗巨细胞病毒(CMV)药物必须静脉给药，因为口服给药会导致无法测量或几乎无法测量的血浆水平。在低pH条件下，磷甲酸钠通过酸催化的脱羧基分解；因此，口服生物利用度较低可能是由于磷甲酸钠在胃酸中的分解所致。我们评估了用雷尼替丁提高胃的pH值是否会促进6名无症状的HIV感染者对口服磷甲酸钠的吸收。在一项随机、双盲、交叉研究中，每个志愿者都接受了两次4000毫克(60毫克/公斤)的口服磷甲酸钠，在此之前，在随机、双盲、交叉研究中，先静脉滴注雷尼替丁50毫克D5W或单独D5W 20分钟。胃内pH监测显示，受试者在服用雷尼替丁之前有胃酸产生(pH<；2.0)的证据，在服用雷尼替丁后胃酸(pH>；6.0)升高。大多数磷甲酸钠血浆浓度均低于检出限(33μM)，D5周和雷尼替丁分别为4/30和8/30。雷尼替丁处理后，磷甲酸钠的尿得率增加。雷尼替丁处理后24小时尿中药物平均回收率为9.9%，而D5W处理后为6.2%(P<；0.03)。我们估计在24小时内尿液中9.9%的回收率相当于口服剂量的17.1%。尽管雷尼替丁的预处理提高了生物利用度，但吸收程度仍然不足以达到治疗CMV或抗阿昔洛韦疱疹病毒的有效血浆浓度。我们得出结论，胃酸是磷甲酸钠吸收的一个决定因素，尽管不是一个主要因素。即使在胃液pH值升高的情况下服用，口服磷甲酸钠也不太可能在临床上有用。
For systemic use, the anti-cytomegalovirus (CMV) agent foscarnet must be given intravenously because oral administration results in unmeasurable or barely measurable plasma levels. At low pH, foscarnet decomposes via an acid-catalyzed decarboxylation; therefore, poor oral bioavailability might be due to decomposition of foscarnet in gastric acid. We evaluated whether increasing gastric pH with ranitidine would enhance the absorption of oral foscarnet in six asymptomatic HIV-infected individuals. Each volunteer received two oral 4000-mg (60 mg/kg) doses of foscarnet, preceded intravenously by a 20-min infusion of either ranitidine 50 mg in D5W or D5W alone in a randomized, double-blind, cross-over study. Intragastric pH monitoring revealed that subjects had evidence of gastric acid production (pH<2.0) prior to administration of ranitidine and increased gastric pH (pH>6.0) following ranitidine administration. Most foscarnet plasma levels were below the assay limit of detection (33 μM) with only 4/30 levels detectable after D5W and 8/30 after ranitidine. Urinary recovery of foscarnet increased after ranitidine pretreatment. A mean recovery of 9.9% of the drug was realized in the urine in 24 h following ranitidine pretreatment compared to 6.2% of the dose after D5W pretreatment (P<0.03). We estimate that 9.9% recovery in the urine in 24 h is equivalent to absorption of 17.1% of the oral dose. In spite of the enhanced bioavailability associated with ranitidine pretreatment, the degree of absorption is still insufficient to achieve effective plasma concentrations for the treatment of CMV or acyclovir-resistant herpes viruses. We conclude that gastric acidity is a determinant of foscarnet absorption, albeit not a major one. Oral foscarnet is unlikely to be clinically useful even if administered in the setting of increased gastric pH.