A double-blind, placebo-controlled study to assess tolerability, pharmacokinetics and preliminary pharmacodynamics of single escalating doses of Z13752A, a novel dual inhibitor of the metalloproteases ACE and NEP, in healthy volunteers

AIMS: The objective of this study was to evaluate the tolerability of a novel dual ACE-NEP inhibitor, Z13752A, after the oral administration of rising single doses in healthy volunteers. This study was also a preliminarily investigation of Z13752A pharmacodynamics (PD) and pharmacokinetics (PK). METHODS: In this randomized, placebo-controlled, sequential study, two alternating panels of eight healthy male volunteers each (six subjects receiving the active treatment + two subjects receiving placebo) were treated with increasing oral doses of Z13752A: 10, 50, 200, and 600 mg were given to panel I and 20, 100, 400 and 800 mg were given to panel II. The study was double-blind relative to placebo or active treatment, and was open with respect to the dose levels. The same volunteer received placebo only once. RESULTS: Single oral doses of Z13752A, as high as 800 mg, were well tolerated. Only six mild-to-moderate adverse events mainly headache, were reported and appeared to be of little clinical relevance. After administration of 200, 400, 600 and 800 mg of Z13752A, a nonsignificant fall in diastolic blood pressure was detected, in both the standing and supine position. After single oral doses of Z13752A, ACE inhibition appeared to be significant at all the doses tested, linearly correlated with the dose and was almost complete at doses > or = 100-200 mg. NEP inhibition was indicated by elevation of ANP and cGMP plasma concentrations in almost all subjects. In the 200-800 mg dose range, Z13752A produced a 50-100% increase of plasma cGMP levels and a 50-80% elevation in urinary cGMP concentrations. Detectable plasma levels of Z13752A were found in all the treated subjects. Z13752A was well and rapidly absorbed, with peak concentrations reached approximately 2.5 h after administration. The mean apparent elimination half-life from plasma was approximately 12 h. The pharmacokinetics of Z13752A after single oral doses were characterized by low intersubject variability and appeared to be dose-independent. CONCLUSIONS: Z13752A showed a good single dose tolerability profile at doses up to 800 mg. The pharmacokinetic data indicate that Z13752A administered orally is rapidly absorbed and available to the systemic circulation in humans. The relatively slow clearance indicates that a once-a-day dose regimen could be considered for Z13752A.     

Lack of effect of amoxycillin on the absorption of ofloxacin

Summary Amoxycillin and ofloxacin are both well absorbed after oral administration, despite being hydrophilic. We have studied the possibility of competition between these two drugs for a carrier-mediated transport system, since both drugs are absorbed by saturable processes in the rat small intestine.Oral doses of amoxycillin (3 g) and ofloxacin (400 mg) were given separately and in combination to six healthy volunteers. Blood samples were taken over 30 h and plasma concentrations of the respective drugs were measured by HPLC.Amoxycillin did not alter the pharmacokinetics of ofloxacin.     

The pharmacokinetics and tolerability of the oral neuraminidase inhibitor oseltamivir (Ro 64-0796/GS4104) in healthy adult and elderly volunteers

The tolerability and pharmacokinetics of Ro 64-0802, a potent, selective inhibitor of influenza neuraminidase, and its oral prodrug oseltamivir were investigated in three double-blind, placebo-controlled studies. Two studies involved healthy adult volunteers (18-55 years) (n = 48) who received single (20-1000 mg) or bid doses (50-500 mg) (n = 32) of oseltamivir or placebo for 7 days. Healthy elderly volunteers (> or = 65 years) (n = 24) received oseltamivir 100 to 200 mg bid or placebo for 7 days in a third study. Measurable plasma concentrations of the active metabolite appeared rapidly in plasma and were significantly higher and longer lasting than those of oseltamivir. Pharmacokinetics of both compounds were linear. Multiple-dose exposure was predictable from single-dose data, and steady-state plasma concentrations were achieved within 3 days of bid drug administration. Oseltamivir was well tolerated at single doses of up to 1000 mg and twice-daily doses of up to 500 mg. Adverse events were mild in intensity. Exposure to both prodrug and active metabolite was increased in elderly patients by approximately 25%. However, due to the wide safety margin of both compounds, no dose adjustment is necessary for elderly patients.     

Pharmacokinetics of L-FMAUS, a new antiviral agent, after intravenous and oral administration to rats: contribution of gastrointestinal first-pass effect to low bioavailability

The pharmacokinetics of L-FMAUS after intravenous and oral administration (20, 50 and 100 mg/kg) to rats, gastrointestinal first-pass effect of L-FMAUS (50 mg/kg) in rats, in vitro stability of L-FMAUS, blood partition of L-FMAUS between plasma and blood cells of rat blood, and protein binding of L-FMAUS to 4% human serum albumin were evaluated. L-FMAUS is being evaluated in a preclinical study as a novel antiviral agent. Although the dose-normalized AUC values of L-FMAUS were not significantly different among the three doses after intravenous and oral administration, no trend was apparent between the dose and dose-normalized AUC. After oral administration of L-FMAUS (50 mg/kg), approximately 2.37% of the oral dose was not absorbed, and the extent of absolute oral bioavailability (F) was approximately 11.5%. The gastrointestinal first-pass effect was approximately 85% of the oral dose. The first-pass effects of L-FMAUS in the lung, heart and liver were almost negligible, if any, in rats. Hence, the small F of L-FMAUS in rats was mainly due to the considerable gastrointestinal first-pass effect. L-FMAUS was stable in rat gastric juices. The plasma-to-blood cells partition ratio of L-FMAUS was 2.17 in rat blood. The plasma protein binding of L-FMAUS in rats was 98.6%.     

Preliminary studies of absorption and excretion of benoxaprofen in man.

1 Benoxaprofen is a new acidic anti-inflammatory compound which was well absorbed after oral administration to man. 2 Single doses of 100, 200 and 400 mg produced mean peak concentrations in the plasma of 13.0, 33.5 and 45.3 microgram respectively, and the plasma half-life of the compound was between 30 and 35 hours. 3 Multiple dosing with 25 and 50 mg every 24 h achieved an equilibrium conentration in the plasma after 6-8 days, while dosing with 100 mg every 12 h enabled equilibrium to be reached in 3-6 days. Plasma concentrations between 35 and 45 microgram/ml were achieved by giving 100 mg doses every 12 hours. 4 Absorption of benoxaprofen was delayed when the drug was given with food, but the total amount absorbed remained the same. 5 The effect of milling the material to small particle size (19 micron) was to increase the rate of absorption compared to that of unmilled material (58 micron). 6 Benoxaprofen was well tolerated by healthy male subject in the doses given.     

The pharmacokinetics and pharmacodynamics of a new thromboxane synthetase inhibitor, 6-(1-imidazolylmethyl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (DP-1904) in man after repeated oral doses

The pharmacokinetics of DP-1904, a new potent and selective thromboxane synthetase inhibitor, and its effects on ex-vivo prostanoid formation have been studied in groups of Japanese normal male volunteers, who received repeated oral doses of 200 mg every 12 h for 4 doses, or 400 mg every 24 h for 2 doses, or 200 mg every 12 h for 14 doses. The drug was well tolerated by all subjects without evidence of adverse reactions. Repeated administration showed no significant changes in half-lives, tmax values, cmax values and AUC values. DP-1904 did not exhibit time-dependent kinetics. Its plasma levels were lower than the quantifiable level (50 ng mL-1) at 12 h after each dose. These data suggest no significant accumulation of DP-1904 in normal volunteers. DP-1904 reduced the serum thromboxane B2 by about 80% during the medication, the serum concentrations returning to about 44, 75 and 20% of the predrug control values at 36 h after the last 200 mg doses and 48 h after the last 400 mg dose.     

Pharmacodynamics, pharmacokinetics and safety profile of the new platelet-activating factor antagonist apafant in man.

Platelet-activating factor (PAF) is a unique phospholipid mediator with multifunctional properties. Evidence generated in experimental studies suggests that PAF plays a pathogenetic role in anaphylactic, inflammatory and immunogenic reactions. Apafant (WEB 2086, CAS 105219-56-5), a novel synthetic PAF receptor antagonist, was administered to a total of 101 healthy volunteers within 5 studies to investigate its pharmacologic activity, pharmacokinetic behaviour and safety profile. Pharmacologic activity was monitored by inhibition of 5 x 10(-8) mol/l PAF-induced platelet aggregation ex vivo. The following treatment schedules were studied: oral single dose 1.25 to 400 mg; oral multiple dose 100 mg t.i.d. over 7 days; i.v. infusion 0.5 to 50 mg (over 30 min); inhalative administration up to 1.0 mg. PAF induced platelet aggregation was virtually completely inhibited by single oral doses of 20 mg upwards, throughout during the multiple oral dose study, at all dose levels tested in the i.v. study and (significantly but not completely) at 0.5 and 1.0 mg in the inhalative study. Following oral administrations (capsules) apafant is absorbed rapidly (tmax 1 to 2 h), there is linear pharmacokinetics for the mean plasma concentrations of apafant measured by RIA as well as for the areas under the curve (AUCs). Approximately 60% of apafant is bound to plasma protein, the mean volume of distribution is 28 l, about 44% of an oral dose is excreted in the urine, the mean renal clearance is 192 ml/min. No accumulation of the drug occurred in volunteers with normal kidney function. No clinically relevant drug related adverse events or changes in laboratory or vital parameters such as blood pressure, heart rate, respiratory rate and ECG were observed.(ABSTRACT TRUNCATED AT 250 WORDS)     

The objective and timing of drug disposition studies, appendix III. Diethylpropion and its metabolites in the blood plasma of the human after subcutaneous and oral administration.

Diethylpropion hydrochloride is an effective anorexiant at the recommended dose of 25 mg three times a day. Previous work in volunteers to evaluate the effects of much larger doses showed that 400 mg given orally was equipotent with 600 mg subcutaneously in terms of subjective and physiologic effects, i.e., the drug was more potent orally than subcutaneously. In one volunteer, blood level studies after a 600-mg subcutaneous dose showed concentrations of unchanged diethylpropion in the plasma about three times as high as those found after the equipotent 400 mg oral dose. In nine other volunteers, the plasma concentrations of unchanged diethylpropion found after a 75-mg oral dose was less than 1/100 of that observed after a 400-mg oral dose. These observations suggest a rapid but limited metabolic capacity for conversion of diethylpropion to its metabolites. The data indicate that the metabolites, rather than the parent drug, are responsible for the pharmacologic responses seen with doses much larger than those necessary for inducting anorexia.     

Pharmacokinetics of rokitamycin after single administration to healthy volunteers

The pharmacokinetics of rokitamycin tablets were studied in 12 healthy volunteers in a randomized cross-over design. The doses tested were 200 mg, 300 mg, 400 mg and 600 mg, as single oral administration. Rokitamycin was absorbed quickly with Tmax for all doses around 30 min after drug intake. Total AUC and Cmax values were linearly related to the administered dose. The buffer formulation determined a low interindividual variation. The overall findings show a good similarity with the data obtained in Japanese subjects. Tolerability was very good.     

Clinical pharmacology of moclobemide, a new reversible monoamine oxidase inhibitor

The clinical pharmacology of the new reversible monoamine oxidase (MAO) inhibitor, moclobemide, was examined in three separate studies in healthy male volunteers. In a single oral dose study, moclobemide (25-150 mg) was rapidly absorbed from the gastrointestinal tract and had a relatively short plasma half-life (mean 1.3 h after 150 mg). A decrease in the plasma concentrations of the noradrenaline metabolite 4- hydroxy-3-methoxyphenylglycol (HMPG), however, indicated a longer time to peak pharmacodynamic effect and longer duration of activity. Assay of platelet MAO activity did not reveal any evidence of irreversible inhibition of the B form of the isoenzyme. Single oral doses of moclobemide (150 and 300 mg) significantly lowered the threshold to the cardiovascular effects ('cheese reaction') of intravenous tyramine. However, after repeated administration of 100 mg three times daily for over 2 weeks, moclobemide caused significantly less potentiation than did phenelzine (15 mg three times per day) on the cardiovascular effects of oral tyramine, a clinically more relevant model. The MAO-B inhibitor, selegiline (5 mg once daily), also lowered the oral tyramine threshold significantly. Moclobemide was generally well tolerated by these healthy volunteers.     

Single intravenous and oral doses of fenflumizole: pharmacokinetics and effects on prostanoid formation

Fenflumizole is a substituted triaryl-imidazole with anti-inflammatory activity. Its disposition in man was studied after single intravenous and oral doses to 8 healthy male volunteers. Formation of the prostanoids thromboxane B2 (TXB2) and 6-keto-prostaglandin F1 alpha (6-k-PGF1 alpha) in clotting blood was studied concomitantly. The pharmacokinetics after intravenous doses (0.1 mg/kg) could be fitted to a three compartment model and the half-lives (t 1/2) corresponding to the three phases were 2 min., 1 hour and 15 hours, respectively. The volume of distribution was 386 l and the plasma clearance 0.5 l per min. Oral doses (0.5 mg/kg) were rapidly absorbed (t 1/2 = 0.2 hr) and the following elimination from plasma had two phases with half-lives of 1 hour and 14 hours. Bioavailability was 50% due to a pronounced first-pass effect. The two metabolites mono- and didemethylfenflumizole were detected after both oral and intravenous doses and their maximum plasma concentrations occurred after 1-2 hours irrespective of the administration route. A concentration dependent depression of prostanoid formation was seen, the IC50 for TXB2 and 6-k-PGF1 alpha being 19 and 53 ng/ml respectively.     

Diethanolamine absorption,metabolism and disposition in rat and mouse following oral,intravenous and dermal administration

1. The disposition of [¹⁴C]diethanolamine (DEA) (1) was determined in rat after oral, i.v. and dermal administration, and in mouse after dermal administration. 2. Oral administration of DEA to rat was by gavage of 7?mg/kg doses once and after daily repeat dosing for up to 8 weeks. Oral doses were well absorbed but excreted very slowly. DEA accumulated to high concentrations in certain tissues, particularly liver and kidney. The steady-state of bioaccumulation was approached only after several weeks of repeat oral dosing, and the half-life of elimination was approximately 1 week. 3. DEA was slowly absorbed through the skin of rat (3-16% in 48?h) after application of 2-28?mg/kg doses. Dermal doses ranging from 8 to 80?mg/kg were more readily absorbed throughmouseskin(25-60%) in 48?h of exposure,withthe percent of the applied dose absorbed increasing with dose. 4. Single doses (oral or i.v.) of DEA were excreted slowly in urine (c. 22-25% in 48?h) predominantly as the parent compound. There was minimal conversion to CO₂ or volatile metabolites in breath. The profile of metabolites appearing in urine changed after several weeks of repeat oral administration, with significant amounts of N-methylDEA and more cationic metabolites appearing along with unchanged DEA.     

Determination of acyclovir in plasma by solid-phase extraction and column liquid chromatography

After oral administration, valacyclovir, the L-valyl ester of acyclovir, converts to the antiherpes virus drug, acyclovir. The bioavailability of acyclovir after valacyclovir administration is between 3- to 4.5-fold higher than that achieved after oral acyclovir administration. Therefore, despite the drug's short terminal half-life (3 hours), acyclovir plasma concentrations obtained after oral administration of the prodrug offer a more convenient dosage regimen in patients with herpes zoster than that required after acyclovir administration. Acyclovir is also used for viral infection prophylaxis in patients with hematologic disorders and in those who have undergone solid organ transplantation. We have described a simple and selective liquid chromatographic method for the determination of acyclovir in plasma using a new polymeric reversed-phase sorbent for solid-phase extraction. A mean acyclovir absolute recovery of 90% was found after elution of the drug from the cartridge with the mobile phase. This procedure allowed us to measure 62.5 ng/mL of acyclovir with an acceptable precision using a plasma volume of 250 microL, and no drug was found to interfere with the assay. This method is suitable for the therapeutic monitoring of acyclovir in patients who have been given a wide variety of coadministered drugs.     

The effect of the converting enzyme inhibitor HOE 498 on the renin angiotensin system of normal volunteers

Summary The converting enzyme inhibitor HOE 498 was evaluated in 12 normotensive male volunteers aged 21 to 26. The efficacy of single 5, 10 or 20 mg oral doses in blocking the pressor response to exogenous angiotensin I was tested in 3 of the subjects. All 3 doses of HOE 498 reduced the pressor response to exogenous angiotensin I to below 50% of control within 1,5 h following administration of the drug. Plasma renin and converting enzyme activity, blood angiotensin I, as well as plasma angiotensin II and aldosterone were measured serially before and up to 72 h following oral administration of a single dose of 2.5, 5, 10 or 20 mg of HOE 498 to groups of 5 volunteers each. As expected, blood angiotensin I levels and plasma renin activity rose while plasma converting enzyme activity, plasma angiotensin II and aldosterone concentration fell after administration of the drug. While the dose of 2.5 mg did not reduce plasma converting enzyme activity below 20% of control, the higher doses all resulted in plasma converting enzyme inhibition exceeding 90%. No side-effects were observed. It is concluded that in normal volunteers HOE 498 is an effective potent and long-acting converting enzyme inhibitor. Based on these preliminary findings it is expected that 5 mg HOE 948 will turn out to be adequate for therapeutic use.     

Metabolism and disposition of diethylene glycol in rat and dog.

The disposition of carbon-14-labeled diethylene glycol (DEG) was determined in rats after oral, iv, and dermal administration, and in dogs after oral administration. Oral administration of DEG to rats was by gavage of 50 or 5000 mg/kg doses, or by provision of 0.3 1.0, and 3.0% in drinking water. Oral doses were well absorbed and excreted primarily (approximately 80%) in urine within 24 hr of administration. Greater than half of the dose was excreted unchanged, with 10-30% of the dose appearing as a single metabolite. The metabolite was isolated and characterized by 13C-NMR to be 2-(hydroxy) ethoxyacetic acid (HEAA). Confirmation of identity was provided by synthesis of HEAA and comparison of its NMR spectra and chromatographic behavior with those of the metabolite. Intravenous doses (50 mg/kg) were eliminated by the same routes and at the same rates as those administered orally and exhibited the same metabolic profile. The fate of oral doses of DEG administered to dogs (500 mg/kg) was similar to that of DEG in rats, with about 30% of the administered dose being excreted in urine as HEAA. DEG slowly penetrated the skin of rats after application of 50 mg to a 12-cm2 area. Only about 10% of the dose was absorbed in 72 hr of exposure, and the absorbed dose appeared to have the same fate as doses administered iv or orally. In all studies with rats, excretion of radiolabel in feces and persistence in tissues were low. The highest percentage of conversion to 14CO2 was 7%, found for doses of 0.3% DEG in drinking water.     

Novel Insights to Enhance Therapeutics With Acyclovir in the Management of Herpes Simplex Encephalitis

Acyclovir is an antiviral drug poorly absorbed in the gastrointestinal tract due to its hydrophilicity, with low oral bioavailability (~20%). Although acyclovir is prescribed in the management of herpes simplex encephalitis (HSE), the disease has a poor prognosis, particularly if the treatment is delayed, reaching mortality rates of 70% if left untreated. Thus, high acyclovir doses are administered by intravenous (IV) infusion, usually at a dosage of 10 mg kg^?1 8-hourly in adults with normal renal function. However, the mortality related to HSE treated with acyclovir remains high (~20%) and permanent sequelae are commonly reported after 1 year (~50%). This review analyzed clinical trials following IV acyclovir administration. Novel insights aiming to improve drug bioavailability were reviewed, including acyclovir or its prodrugs, leading to the systemic distribution of the drug or drug targeting. Much research effort has been made to improve antiviral therapy, searching for delivery systems increasing acyclovir bioavailability by non-invasive pathways, such as oral and nasal pathways, or parenterally administered nanotechnology-based systems leading to drug targeting. Nanocarriers administered by non-invasive pathways represent feasible alternatives to treat HSE, even though not be industrially manufactured yet.     

Absolute bioavailability, rate of absorption, and dose proportionality of sulpiride in humans.

The pharmacokinetics of orally administered sulpiride was determined in a series of three studies. In the first study, 12 subjects received an oral solution (200 mg) and an iv dose (100 mg). The second study also included an iv dose, and examined the absorption of 200-, 300-, and 400-mg doses given as 50-mg capsules to six subjects. The third study compared the bioavailability of a 200-mg capsule dose with a 200-mg im dose in eight subjects. The concentration of sulpiride in plasma, red blood cells, and urine was measured by HPLC. The disposition of the drug was generally best described by a two-compartment pharmacokinetic model, with absorption appearing to occur by two sequential zero-order processes. The fraction of dose absorbed after oral administration was approximately 30% based on plasma and urine data. After the 200-mg dose, the mean elimination half-life was 7.0 h, and the mean residence time was 8.4 h. For each subject, total clearance, corrected for the fraction absorbed, and renal clearance were similar. The dose proportionality study demonstrated linear disposition kinetics.     

Plasma levels and beta-adrenoceptor blockade with acebutolol, practolol and propranolol in man.

1 The degree of beta-adrenoceptor blockade of isoprenaline-induced tachycardia has been determined in three healthy volunteers after the administration of single oral doses of acebutolol, practolol or propranolol. 2 Plasma levels of these drugs were determined either colorimetrically (acebutolol and practolol) or fluorimetrically (propranolol). The colorimetric assay of acebutolol in plasma is fully described but the other drugs were assayed by published methods. 3 The degree of beta-adrenoceptor blockade and the plasma level for acebutolol and practolol were well correlated, whereas in the case of propranolol correlation was poor, due in part to the presence in plasma of active metabolites not detected by the fluorimetric assay. The plasma levels of practolol and propranolol are in agreement with those previously reported. 4 The maximum cardiac beta-adrenoceptor blockade achieved in this study with the respective single oral doses of acebutolol (300 mg), practolol (400 mg) or propranolol (40 mg) were similar in each of the three subjects. Therefore the beta-adrenoceptor blocking potencies of these drugs against isoprenaline-induced tachycardia are inversely related to these doses; indicating that propranolol is 7-8 times more potent than acebutolol and the latter slightly more potent than practolol.     

Pharmacological investigations of a new renin inhibitor in normal sodium-unrestricted volunteers.

1. CGP 38 560 A, a low-molecular-weight, non-peptidic renin inhibitor, was well tolerated upon intravenous and oral administration to recumbent healthy volunteers on an unrestricted-sodium diet. 2. After intravenous infusion over 30 min at a rate of 100 ml h-1, doses of 50, 125 and 250 micrograms kg-1 appear to induce a long-lasting inhibition of plasma renin activity. Plasma angiotensin II was decreased in a dose-dependent manner during the infusion and thereafter reverted to the initial level. A concomitant dose-related increase in active plasma renin was observed. Blood pressure was unaffected. The plasma levels of CGP 38 560 reached during infusion were at least 2000-fold higher than the theoretical inhibitory concentration based on in vitro results. 3. After oral administration in doses of 50, 100 and 200 mg CGP 38 560 A, inhibition of plasma renin activity was observed, but plasma active renin was unchanged. Blood pressure also remained unaffected. 4. CGP 38 560 was rapidly cleared from plasma with a half-life of 7.6 min for the first phase and 63 min for the second phase. Plasma levels were 100-fold lower after oral administration than after infusion, indicating a low degree of absorption (less than 1% oral bioavailability).     

Pharmacokinetics of morphine-6-glucuronide following oral administration in healthy volunteers

Aim After oral administration, morphine-6-glucuronide (M6G) displays an atypical absorption profile with two peak plasma concentrations. A proposed explanation is that M6G is hydrolysed to morphine in the colon, which is then absorbed and subsequently undergoes metabolism in the liver to morphine-3-glucuronide (M3G) and M6G. The aims of this study were to confirm and elucidate the biphasic absorption profile as well as clarify the conversion of M6G to morphine after a single oral administration of M6G in healthy volunteers. Methods The study was conducted accordingly to a nonblinded, randomised, balanced three-way crossover design in eight healthy male subjects. The subjects received 200 mg oral M6G, 50 mg oral M6G and 30 mg oral morphine. Blood samples were collected until 72 h after M6G administration and until 9 h after morphine administration. Paracetamol and sulfasalazine were coadministered with M6G as markers for the gut contents reaching the duodenum and colon, respectively. Results The plasma concentration peaks of M6G were seen at 4.0 (2.0–6.0) and 18 (12.0–24.0) h after 200 mg M6G and at 3.5 (2.0–6.0) and 21.3 (10.0–23.3) h after 50 mg M6G, which was in agreement with previously published results. The K_{M6G_abs}/K_{M6G_M6G} ratio was found to be 10. Conclusion The pharmacokinetic profile of M6G after oral administration was confirmed and with the presence of M3G and morphine in plasma after oral administration of M6G, proof seems to be found of the constant and prolonged absorption of M6G. The K_{M6G_abs}/K_{M6G_M6G} ratio of 10 indicates that the second absorption peak of M6G consists of approximately 10 times more absorbed M6G than reglucuronidated M6G. However, further studies are required to determine the precise kinetics of the second absorption peak.