Portal vein dosing

The estimation of in vivo hepatic CL requires cannulation of the portal vein. By comparing AUC of portal vein dosing and systemic dosing, CLh can be estimated with the following equations ... 

Al JCpv" and AlJC-f are AUCs of systemic sampling from portal vein dosing and systemic IV dosing, respectively Qh is the standard liver blood flow listed in Table 3.2... 

For the majority of drugs, the preferred administration route is by oral ingestion which requires good intestinal absorption of drug molecules. Intestinal absorption is usually expressed as fraction absorbed (FA), expressing the percentage of initial dose appearing in a portal vein [15]. 

The use of hepatic portal vein-cannulated animals can be helpful in determining specific causes of poor bioavailability. After oral dosing, the total bioavailability of a compound is normally calculated as ... 

Using an alternative method, generally referred to as an indirect method, Eg may also be estimated following i.d. dosing alone and sampling portal blood and the systemic circulation concurrently. The mass of drug appearing in the portal vein (Ma) is defined as follows ... 

A % Percentage of dose absorbed as measured in portal vein... 

If after single dose administration, the blood samples are not collected at time intervals, which allow for a description of the whole plasma concentration time course, including the absorption, distribution, and elimination phase, the information obtained is limited. In particular, data should be available in the hrst hours after administration to cover the absorption phase. If measurements of the parent compound and its metabolite(s) are made in this period, this will allow assessment of an extensive first pass effect, i.e., when a substance after oral administration is transported via the portal vein to the liver where metabolism takes place before the substance enters the systemic circulation. 

The hepatic first-pass effect can be avoided to a great extent by use of sublingual tablets and transdermal preparations and to a lesser extent by use of rectal suppositories. Sublingual absorption provides direct access to systemic—not portal—veins. The transdermal route offers the same advantage. Drugs absorbed from suppositories in the lower rectum enter vessels that drain into the inferior vena cava, thus bypassing the liver. However, suppositories tend to move upward in the rectum into a region where veins that lead to the liver predominate. Thus, only about 50% of a rectal dose can be assumed to bypass the liver. 

In rats burned once with 29 or 100 mg/kg/day white phosphoms, an increase in ALT levels, necrosis, ballooning degeneration of hepatocytes, and microthrombi in the portal veins have been observed (Ben-Hur and Appelbaum 1973 Ben-Hur et al. 1972). In rabbits burned by white phosphoms (dose not reported), serum calcium and phosphoms levels were normal, and no morphological damage was observed (Bowen et al. 1971). No longer-term human and animal studies examining hepatic effects were found. 

Where /a is the fraction of the dose of the drug which enters the gut wall (drug may be lost by decomposition in the gut lumen [2] or it may not be able to get across the gut wall), Fg is the fraction of drug which escapes metabolism in the gut wall and enters the portal vein and Fh is the fraction of the drug that enters the liver and escapes metabolism, entering systemic circulation. 

Menaquinones are absorbed mainly from the terminal ileum, where bile salts are present, into the hepatic portal vein. Litde of the menaquinones formed by colonic bacteria can be absorbed, because they remain tightly bound to bacterial cell membranes in the absence of bile salts. About 90% of the total liver content of vitamin K is menaquinones 7 to 13, and the hepatic pool of phylloquinone turns over considerably faster than that of menaquinones. Sixty percent to 70% of the daily intake of phylloquinone is excreted, mainly as conjugates in the bile, and the half-life of a tracer dose of phylloquinone is only about 17 hours. 

The amount of verapamil presented to the liver, and its effective concentration in the region of the hepatic er zymes soon after oral dosing, are related to the rate at which verapamO is absorbed from the gastrointestinal tract into the portal vein and to the flow rate of blood in the portal vein to the liver. For instance, by hypothesizing a Michaelis-Menten metabolic process, when the absorption rate is slow and concentrations in the portal vein and liver are low, the hepatic metabolism of both enantiomers will be approximately first-order. Under these conditions, the K S ratio of the umnetabolized enantiomers leaving the liver will be closely related to the ratio of the Michaelis-Menten saturation constants (K ) for the enantiomers. The observed more rapid metabolism of S-verapamil than R-verapamil (i.e., S-verapamil has the lower systemic concentrations) is consistent with the lower reported for S-verapamil (16). 

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