Melander A, McLean A
Clin Pharmacokinet. 1983 Jul-Aug;8(4):286-96. doi: 10.2165/00003088-198308040-00002.
Many drugs have a low degree of oral bioavailability even though their gastrointestinal absorption is complete. This is because they undergo extensive presystemic metabolic transformation during the first passage of the drug through the gastrointestinal mucosa and the liver. In addition to effects on the absorption of some drugs, food intake has been found to influence the bioavailability of drugs with extensive presystemic metabolic clearance. Extensive presystemic clearance occurs commonly with compounds that are lipophilic bases, e.g. propranolol and amitriptyline, but rarely if ever with lipophilic acids, e.g. salicylic acid and penicillin, except for esters of such acids, e.g. acetylsalicylic acid (aspirin) and pivampicillin. While presystemic clearance of (esterified) acidic drugs is unaffected by food, concurrent food intake markedly reduces presystemic clearance, and thus enhances bioavailability, of several lipophilic bases. Among these are propranolol, metoprolol, labetalol, dixyrazine and hydralazine, which are presystemically metabolised by hydroxylation, glucuronidation and acetylation enzymes systems. In contrast, the bioavailability of lipophilic bases which undergo presystemic dealkylation (amitriptyline, codeine, dextropropoxyphene, prazosin, zimelidine) is unaffected by concurrent food intake. Food intake reduces presystemic clearance of hydralazine and propranolol when these drugs are administered in conventional rapid-release tablets but not when they are given in slow-release formulations. Likewise, coadministration of hydralazine reduces presystemic clearance of rapid-release but not slow-release propranolol. These and other observations favour the view that food may reduce presystemic clearance of (certain) lipophilic basic drugs via transient, complex effects on splanchnic-hepatic blood flow and/or shunt processes, and that the extent of this effect is influenced by the rate of drug delivery to the liver. In addition, these findings refute the notion that the reduced presystemic clearance results from (long-lasting) hepatic enzyme inhibition by some nutrient. On the other hand, repeated intake of specific nutrients (protein) and food contaminants (benzpyrene) can enhance presystemic drug clearance by enzyme induction. Thus, food may exert a dual effect on presystemic drug clearance. A complete evaluation of the influence of food on presystemic drug clearance necessitates bioavailability studies carried out following both single and repeated meals, including different kinds of food prepared by various cooking methods. The influence of food on the presystemic clearance of drugs is most likely to be clinically relevant with drugs having narrow therapeutic margins and/or steep dose-response curves.
许多药物尽管其胃肠道吸收完全，但口服生物利用度却很低。这是因为它们在药物首次通过胃肠道黏膜和肝脏时会经历广泛的首过代谢转化。除了对某些药物的吸收有影响外，人们还发现食物摄入会影响具有广泛首过代谢清除的药物的生物利用度。首过清除广泛常见于亲脂性碱类化合物，如普萘洛尔和阿米替林，但亲脂性酸类，如水杨酸和青霉素，很少发生首过清除，不过此类酸的酯类，如乙酰水杨酸（阿司匹林）和匹氨西林除外。虽然（酯化）酸性药物的首过清除不受食物影响，但同时摄入食物会显著降低几种亲脂性碱的首过清除，从而提高其生物利用度。其中包括普萘洛尔、美托洛尔、拉贝洛尔、地昔帕明和肼屈嗪，它们在首过代谢过程中会被羟基化、葡萄糖醛酸化和乙酰化酶系统代谢。相比之下，经历首过脱烷基作用的亲脂性碱（阿米替林、可待因、右丙氧芬、哌唑嗪、齐美利定）的生物利用度不受同时摄入食物的影响。当肼屈嗪和普萘洛尔以传统速释片给药时，食物摄入会降低它们的首过清除，但以缓释制剂给药时则不会。同样，同时服用肼屈嗪会降低速释普萘洛尔的首过清除，但不会降低缓释普萘洛尔的首过清除。这些以及其他观察结果支持这样一种观点，即食物可能通过对内脏 - 肝脏血流和/或分流过程产生短暂、复杂的影响来降低（某些）亲脂性碱性药物的首过清除，并且这种影响的程度受药物输送到肝脏的速率影响。此外，这些发现驳斥了首过清除降低是由某些营养素（长期）抑制肝酶所致的观点。另一方面，反复摄入特定营养素（蛋白质）和食物污染物（苯并芘）可通过酶诱导作用增强首过药物清除。因此，食物可能对首过药物清除产生双重影响。要全面评估食物对首过药物清除的影响，需要在单次和多次进餐（包括用各种烹饪方法制备的不同种类食物）后进行生物利用度研究。食物对药物首过清除的影响在治疗窗窄和/或剂量 - 反应曲线陡峭的药物中最有可能具有临床相关性。
