The First Pass Effect

Kwan, K.C. (1997) Oral BioavaUabUity and the First Pass Effect. Drug Metabolism and Disposition, 25(12), 1329-1336. 

Fig. 2 Various routes and pathways by which a drug may be input into the body. The position of one lung is distorted to emphasize that the lungs are in an excellent position for cleansing the blood. The diagram is especially useful in explaining the first-pass effect following oral dosing, for which drug absorbed from the small intestine or stomach must first pass through the liver and, therefore, is subject to metabolism or biliary excretion before reaching the sampleable blood. (From Ref. 2.)...

The first-pass effect has not been extensively evaluated in infants and children. The maturational rate of metabolic pathways would be directly related to the oral bioavailability of a drug subject to first-pass effect. Drugs that undergo glucuronidation during en-terohepatic recirculation may have altered systemic availability in children up to approximately 3 years of age because of delayed maturation of conjugation. 

Current estimates suggest that there are around 30,000 alcohol-related deaths a year in the UK. The NHS (National Health Service) spends over 164m a year treating alcohol-related conditions, and one in four male hospital beds is occupied by someone with an alcohol-related illness. Alcohol adversely aflfects numerous aspects of health, even in those who are only moderate drinkers. However, the effects of high volumes over long periods are certainly the most serious and life-threatening. Alcohol passes through the stomach and small intestine and is then absorbed into the blood stream from where it is metabolised by the liver (the first-pass effect Chapters 3 and 9). 

When the first-pass effect of a drug going through the liver must be avoided, a parenteral route of administration is usually chosen, although a sublingual route or dermal patch will also avoid the first-pass effect. 

The direct transport of absorbed drugs into systemic circulation, effectively by-passing the first-pass effect of the liver and gastrointestinal tract Lower enzymatic activity compared to the gastrointestinal tract or liver Amenability to self-medication, which increases patient compliance Possibility of pulsatile delivery of some drugs to simulate the biorhythmic release of these drugs Lower risk of overdosage Achievement of controlled release... 

When a drug is administered orally, the plasma drug concentration depends on the distribution pathways. For example, if the drug is present in high concentration in the hepatic portal vein, the occurrence of the first-pass effect decreases the amount of drug that reaches the circulation. 

Morphine is glucuronidated in the liver at the phenolic hydroxyl group (C3). Protection of that group with a methyl group, as occurs in codeine and other codeine derivatives such as oxycodone, renders the molecule less susceptible to glucuronidation and decreases the first-pass effect in the liver. It is for this reason that codeine and its derivatives retain activity following oral... 

Nasal administration of butorphanol decreases the onset of action to 15 minutes and decreases the first-pass effect of the drug, which increases bioavailability. Generally the patient sprays a set dose of 1 mg per hour for 2 hours. Tlie duration of action is 4 to 5 hours. The convenience of such administration is a major... 

A brief review of pharmacokinetic principles will place the available data on gender differences in context. Bioavailability, which refers to the amount of drug eventually reaching the systemic circulation, is influenced by absorption, metabolism in the gastrointestinal tract, and the hepatic first-pass effect. The impact of the first-pass effect is greater for drugs that have high hepatic... 

In contrast to oral administration, drugs administered intravenously or intramuscularly directly enter the systemic circulation, avoiding the first-pass effect. 

Diseases that directly affect hepatic integrity include cirrhosis, viral infections, and collagen vascular diseases. Diseases that indirectly affect function include metabolic disorders (e.g., azotemia secondary to renal insufficiency) and cardiac disease. Although decreased left ventricular output can result in a decrease in hepatic arterial flow, right ventricular failure causes hepatic congestion, reducing the first-pass effect and delaying biotransformation. 

Alternative Routes of Administration the First-Pass Effect... 

There are several reasons for different routes of administration used in clinical medicine (Table 3-3)—for convenience (eg, oral), to maximize concentration at the site of action and minimize it elsewhere (eg, topical), to prolong the duration of drug absorption (eg, transdermal), or to avoid the first-pass effect. 

Most opioid analgesics are well absorbed when given by subcutaneous, intramuscular, and oral routes. However, because of the first-pass effect, the oral dose of the opioid (eg, morphine) may need to be much higher than the parenteral dose to elicit a therapeutic effect. Considerable interpatient variability exists in first-pass opioid metabolism, making prediction of an effective oral dose difficult. Certain analgesics such as codeine and oxycodone are effective orally because they have... 

Patients at low risk of developing osteoporosis who manifest only mild atrophic vaginitis can be treated with topical preparations. The vaginal route of application is also useful in the treatment of urinary tract symptoms in these patients. It is important to realize, however, that although locally administered estrogens escape the first-pass effect (so that some undesirable hepatic effects are reduced), they are almost completely absorbed into the circulation, and these preparations should be given cyclically. 

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