First Pass Effect

Phase 2 Reactions

Conjugation with glucuronic acid, sulfate, glutamine, glycine, or glutathione increases the water solubility of the xenobiotic and decreases its biological activity (Fig. 20-17). This is the true detoxification step, since phase 1 reactions often can convert inactive xenobiotics to toxic products.

Ethanol is either a metabolite or a xenobiotic, depending on the amount consumed. When consumed in excess, ethanol is detoxified by the cytochrome P-450 microsomal ethanol oxidizing system (MEOS). However, when consumed in lower amounts, ethanol can enter normal metabolic pathways. In this case, it is metabolized as if it were fat. Two enzymes, alcohol dehydrogenase (cytosol) and acetaldehyde dehydrogenase (mitochondrion), convert ethanol to acetate (Fig. 20-18). This increases the NADH to NAD⁺ ratio in the cytosol and the mitochondrion, which becomes a significant problem in the chronic alcoholic who neglects carbohydrate intake. The shift to fasting metabolism mobilizes free fatty acids to the liver, adding to the acetyl-CoA already produced from ethanol metabolism. As is the case in starvation and untreated diabetes when acetyl-CoA reaches very high levels for a sustained period, acetyl-CoA is shunted into production of ketones with resulting ketoacidosis. The situation is further complicated by the effect of the high NADH to NAD⁺ ratio on pyruvate. Pyruvate would normally be routed to oxalo-acetate for gluconeogenesis during inadequate carbohydrate intake, but instead it is shunted into lactate (Fig. 20-19). This not only produces lactic acidosis, but it leads to hypoglycemia as well.

Metabolism

Nicotine undergoes a large first-pass effect during which the liver metabolizes 80–90%. Small amounts are metabolized in the lungs and kidneys. The major metabolic pathway of nicotine is the C-oxidation to cotinine through a nicotine-Δ-1′-(5′)-iminium ion intermediate catalyzed by CYP2A6. Metabolism also occurs via N-oxidation, and glucuronidation of nicotine, cotinine, and trans-3-hydroxycotinine. Nicotine-1′-N-oxide is reduced to nicotine by bacterial flora in the large intestine via an N-oxide reductase system and subsequently undergoes enterohepatic circulation and repeat metabolism in the liver.

5.2 Metabolism

OBP are metabolized through first-pass effect and phase I and phase II reactions. Studies have reported possible biotransformation of OBP in the intestinal lumen, intestinal cells, blood, and liver. Phase II conjugation reactions are a predominant pathway for the metabolism of simple phenols where 98% of OBP are found as conjugates in plasma and urine [167]. Previous reviews have reported that OBP are primarily glucuronidated as evidenced by detection of their O-glucuronides in plasma [285]. Methyl, sulfate, and glutathionyl conjugates have also been detected in plasma and urine samples following administration of VOO or purified biophenols [167,275,280].

Recently, the metabolism of olive oil phenols by intestinal epithelial cells was investigated by Soler et al.[284]. The major metabolites detected were methylated conjugates, which is in contrast to in vivo studies where the major metabolites are glucuronide conjugates. Soler et al.[284] concluded that this would tend to indicate limited intestinal metabolism in vivo, with the major metabolism occurring in the liver.

Gonzalez-Santiago et al.[288] in a study using purified HT found that the only major metabolite detected in plasma was homovanillic alcohol. The C_max of this metabolite was reached after 16.7 ± 2.4 min, whereas HT reached a C_max of 13.0 ± 1.5 min. At 1 h postadministration neither species was detectable.

There is one issue regarding the metabolism of OBP that seems to have not yet been resolved and this is whether or not conjugated phenols (i.e., secoiridoid phenols and VB)are hydrolysed subsequent to absorption? In case of OL, work by Kendall et al.[277] suggested limited hydrolysis may occur. The metabolism of VB has so far not been investigated.

3 Artemisinin Suppositories

20.2.7 First-Pass Excretion

The first-pass metabolism or the first-pass effect or presystemic metabolism is the phenomenon which occurs whenever the drug is administered orally, enters the liver, and suffers extensive biotransformation to such an extent that the bioavailability is drastically reduced, thus showing subtherapeutic action (Chordiya et al., 2017). It happens when the drug is absorbed through GIT and then via the enterohepatic circulation the drug is absorbed directly into the liver where it undergoes metabolism before being released into the systemic circulation. Generally while designing a drug, some candidates may show good “drug-likeness” but fail due to their biochemical sensitivity towards metabolizing enzymes (Kashyap et al., 2017). Hence, to counteract this first-pass effect the total quantity of metabolized drug is to be calculated and an equivalent amount of excess drug is added to the oral formulation, or an alternative route for administration is recommended to bypass the first-pass metabolism.

Pharmacokinetics

Mianserin is rapidly absorbed and subject to extensive first-pass effects. Its bioavailability is less than 30%. Time to peak is in the region of 3 hours and its half-life is between 10 and 20 hours, though is much extended in the elderly. It is completely metabolised and some products, such as desmethylmianserin, are weakly active.

Trazodone is rapidly absorbed (Tmax = 1–2 hours) and prone to first-pass effects, though 60–80% reaches the systemic circulation. First-pass metabolism may be saturable and plasma levels may follow non-linear pharmacokinetics. Half-life is, for an antidepressant, relatively short at 5–9 hours and excretion is mainly renal. A major metabolite of trazodone, m-chlorophenylpiperazine (m-CPP), has anxiogenic properties which counter the sedative ones of the parent and may produce clinical effects in patients who attain high blood levels (Preskorn 1993).

The main SSRIs are particularly distinguished by variable pharmacokinetics (Table 11.7). All are well, if slowly, absorbed and with fluoxetine may be delayed further by food (Goodnick 1991). Likewise all are extensively metabolised. Both fluoxetine and paroxetine inhibit their own metabolism, so show non-linear kinetics, with increasing doses producing disproportionately large increases in blood levels (Preskorn 1993). In the case of fluvoxamine and paroxetine, metabolism does not appear to result in active metabolites. With the others it does, though the contribution these make to efficacy is not uniform. Fluoxetine's major metabolite, desmethylfluoxetine (‘norfluoxetine’), is roughly equipotent in relation to serotonin reuptake inhibition as the parent but its real importance lies in its exceptionally long elimination half-life (7–15 days). Metabolic parameters may be extended in those with hepatic disease. Desmethylfluoxetine has a major impact on clinical action and on treatment decisions, especially following discontinuation. The mono- and di-methylated metabolites of citralopram are likewise serotonin reuptake inhibitors though are respectively 4 and 13 times less potent than the parent (Boyer & Feighner 1991). Desmethylcitalopram is however considerably more potent than its parent in inhibiting noradrenaline reuptake. The clinical impact of these in vitro findings is likely to be modified by the fact that both metabolites penetrate the brain poorly and although opinions differ, it appears they make little contribution to the therapeutic package. Citralopram's half-life is extended in the elderly. The primary metabolite of sertraline, desmethylsertraline, is ~5–10 times weaker as a serotonin reuptake inhibitor than the parent. Its elimination half-life however is, at over 60 hours, some two and a half times that of sertraline, and while in the elderly this variable is unchanged for sertraline, the half-life of the metabolite is prolonged. For most clinical scenarios it seems unlikely that desmethylsertraline contributes to the therapeutic effect, though there may be some clinical effects in the elderly.

It can be appreciated that for some members of this group steady state can take some time to achieve – citalopram up to a week, fluoxetine 10 days to 3 weeks and for norfluoxetine anything from 4 to 8 weeks.

Venlafaxine is presented as a racemic mix of two active enantiomers. It is readily absorbed with Tmax values in the range of 2–3 hours and first-pass effects are substantial. Protein binding is low compared to other antidepressants (<30%). Its half-life is also short (approximately 5 hours) but that of its major metabolite, O-desmethylvenlafaxine, which is active, is about twice that of the parent. Excretion is almost exclusively renal.

Duloxetine is well absorbed though this may be delayed by food. Cmax is unaffected. Tmax is on average ~6 hours (up to 10 hours after food). The drug is >90% bound to both albumen and α₁-acid glycoprotein. Elimination half-life, at 12 hours on average, is short for once daily dosing. It is extensively metabolised with excretion mainly (~70%) urinary.

Reboxetine is structurally related to both fluoxetine and the now withdrawn viloxazine. It too is presented as a racemic mixture of two enantiomers which appear to have similar kinetics. It is rapidly absorbed (Tmax ~2 hours) with an elimination half-life is in the region of 13 hours. It is highly protein bound, mainly to α₁-glycoprotein. Metabolites are mostly excreted in the urine though some may also be excreted in faeces. Unlike most antidepressants, it appears to have little interaction with the cytochrome P450 system (Dostert et al 1997). This, together with its lack of action on serotonergic systems or against MAO, suggests in theory that combined use may be particularly uncomplicated.

Mirtazapine is again an enantiomeric ‘composite’ ((R)-(−) and (S)-(+)) with cytochrome P450 polymorphisms effecting only the (S)-(+) enantiomer. Absorption is only minimally dependent on gastric contents, with Tmax at around 2 hours. Half-life, which varies from 20 to 40 hours, is comfortably suitable for once daily dosing. It is ~80–85% protein bound with 50% bioavailability largely due to first-pass effects. It does not modify its own metabolism, and interactions with other drugs are rare and clinically insignificant.

S-Adenosylmethionine Treatment in Liver Disease

Bioavailability of orally administered SAMe is poor due to a significant first-pass effect and rapid hepatic metabolism (Loehrer et al., 1997). The half-life of hepatic SAMe under physiological conditions has been estimated to be only about 5 min (Mudd and Poole, 1975). Consistent with this, we previously observed that following SAMe intraperitoneal injection (200 mg/kg), liver SAMe content rose rapidly reaching a peak in 15 min and recovering to basal levels by 4 h after injection (Lu, 2009). Serum concentration of SAMe is low compared to its cellular concentration and has been shown to increase up to 10-fold after its oral administration returning to baseline levels with a half-life of 1.7 h (Loehrer et al., 1997). Nevertheless, SAMe treatment has been shown to reverse NASH in the MCD-diet model (Oz et al., 2006), to prevent CCl₄-induced liver fibrosis in the rat (Corrales et al., 1992) and to attenuate the consequences of ethanol-induced oxidative stress in various experimental models including nonhuman primates (Lieber et al., 1990). SAMe has also been shown to be effective in preventing HCC establishment in the rat although ineffective in treating established HCC because of induction of hepatic GNMT, which prevented SAMe content to reach high enough level needed to kill liver cancer cells (Lu, 2009). One of the chemopreventive actions of SAMe is likely related to its proapoptotic activity in liver cancer cells. SAMe is antiapoptotic in normal hepatocytes but proapoptotic in cancerous hepatocytes (Ansorena et al., 2002). MAT1A is often downregulated in patients with NASH (Moylan et al., 2014). Furthermore, its expression and activity is reduced to undetectable in most cirrhotic livers (Avila et al., 2000; Lee et al., 2004) and is often silenced in HCC (Cai et al., 1996), which correlates with poor prognosis (Frau et al., 2012). These results indicate that MAT1A deficiency is frequent in human chronic liver disease. Accordingly, oral SAMe administration has been shown to increase hepatic GSH content in patients with liver disease (Vendemiale et al., 1989) and to increase survival in patients with alcoholic liver cirrhosis (Mato et al., 1999).

CALCIUM CHANNEL BLOCKING AGENTS

Oral

This is an easy and effective route but is subject to the first-pass effect through the liver, and higher doses are needed in comparison to other formulations.

Transdermal

formulations are in the form of patches and gels. This route may eliminate the risk of thrombosis associated with oral oestrogen.

Subcutaneous implants

Crystalline pellets inserted into the anterior wall or buttock release hormone over several months. Used in women who undergo oophorectomy and hysterectomy, they are usually repeated at 6 months and tachyphylaxis may be a problem.

Vaginal (ring, cream, tablet or pessary)

Low-dose oestrogen therapy is delivered for treatment of urogenital symptoms. If used for long periods, i.e. more than 2 years, progesterone should be added to avoid endometrial hyperplasia.

Others

A nasal spray is available. It delivers 300 micrograms of estradiol daily.

Efficacy of AAADIs

The coadministration of AAADIs together with levodopa produces greater absorption, reduced first-pass effect, and increased entry into brain. Central efficacy of levodopa is generally increased 4–5-fold in the presence of AAADIs. Although levodopa is absorbed from the gut via the large neutral amino acid facilitative transporter (LAT1), its availability for transport is dependent upon decarboxylation that occurs in the GI tract. By inhibiting AAAD, the AAADIs increase LAT1 substrate availability. Similarly, inhibition of AAAD in liver and the rest of the body increases the amount of levodopa available for transport across the BBB by LAT1 found in endothelial cells in the BBB. As a result, a significantly larger fraction of levodopa is available for entry into the brain in the presence of AAADIs. Since AAADIs at administered doses used clinically do not enter the brain in the presence of an intact BBB, levodopa is transported into brain where it can be decarboxylated to DA by AAAD present in neurons and astrocytes.

The AAADIs competitively inhibit AAAD in a dose-dependent fashion. Prior to the advent of AAADIs, inhibition of AAAD was achieved somewhat by depleting pyridoxine in the patient's diet, although the clinical benefit was always controversial. This approach is not needed if AAADIs are coadministered with levodopa. Both the AAADIs have longer plasma half-lives than levodopa, and as a result, accumulate over the day under the multiple daily dosing regimens generally used clinically. Initial administration of low doses of the combination formulation can result in inadequate AAAD inhibition resulting in peripheral side effects. This problem can be averted by prescribing a higher ratio of AAADI/levodopa in the combination formulation. Carbidopa is available as a monotherapy to supplement decarboxylase inhibition when patients exhibit peripheral side effects following combination therapy.