Hypericin pharmacokinetics

The pharmacokinetics of hypericin and pseudohypericin piasma have been studied as weii (Brockmoiier et ai. 1997). Human subjects receiving piacebo, or 900, 1800, or 3600 mg of a standardized hypericum extract (LI 160), which contained 0, 2.81, 5.62, and 11.25 mg of totai hypericin and pseudohypericin, achieved maximum total plasma concentrations at 4 hours (0.028, 0.061, and 0.159 mg/L, respectively). The half-lives of absorption, distribution, and elimination were 0.6, 6.0, and 43.1 hours, respectively, using 750 pg of hypericin, and are slightly different for 1578 pg of pseudohypericin (1.3, 1.4, and 24.8 hours, respectively) (Kerb et ai. 1996). The systemic availability of the hypericum extract LI 160 is between 14 and 21%. Comparable results are found in another study using LI 160 (Staffeldt et ai. 1994). Long-term dosing of 3 x 300 mg per day showed that steady-state levels of hypericin are reached after 4 days. 

Thus, the long tradition of hypericum as a treatment for depression has been well supported by modern scientific research. Several active constituents have been identified, including naphthodianthrones (e.g., hypericin), phloroglucinols (e.g., hyperforin) and flavonoids (amentoflavone). Research has delineated its pharmacokinetic properties, and many of its neurochemical mechanisms have been identified enhancing monoamine... 

Kerb R, Brockmoiier J, Staffeldt B, Ploch M, Roots I. (1996). Single-dose and steady-state pharmacokinetics of hypericin and pseudohypericin. Antimicrob Agents Chemother. 40(9) 2087-93. Kim HL, Streltzer J, Goebert D. (1999). St. John s wort for depression a meta-analysis of well-defined clinical trials. J Nerv Ment Dis. 187(9) 532-38. 

Staffeldt B, Kerb R, Brockmoller J, Ploch M, Roots I. (1994). Pharmacokinetics of hypericin and pseudohypericin after oral intake of the hypericum perforatum extract LI 160 in healthy volunteers. J Geriatr Psychiatry Neurol. 7(suppl 1) S47-53. 

It is not possible to discuss pharmacokinetics when the active compound or compounds of St. John s wort are not known. The half-life of hypericin and hyperforin have been estimated at between 6 and 9 hours, with peak plasma concentrations at about 2-3 hours after administration. Some of the ingredients of Hypericum extracts are metabolized in the liver. 

Single- and multiple-dose pharmacokinetic studies with extracts of SJW were performed in rats and humans, which focused on the determination of plasma levels of the naphthodianthrones hypericin and pseudohypericin and the phloroglucinol derivative hyperforin. Results from pharmacokinetic... 

A placebo-controlled, randomized clinical trial with monitoring of hypericin and pseudohypericin plasma concentrations was performed to evaluate the increase in dermal photosensitivity in humans after application of high doses of SJW extract (Table 2) (73). The study was divided into a single-dose and a multiple-dose part. In the single dose crossover study, each of the 13 volunteers received either placebo or 900, 1800, or 3600 mg of the SJW extract LI 160. Maximum total hypericin plasma concentrations were observed about four hours after dosage and were 0, 28, 61, and 159ng/mL, respectively. Pharmacokinetic parameters had a dose relationship that appeared to follow linear kinetics (73). 

Pharmacokinetics, safety, and antiviral effects of hypericin were studied in patients with chronic hepatitis C infection (Fig. 4) (71). The patients received an eight-weeks course of 0.05 and 0.10 mg/kg hypericin orally once a day. The pharmacokinetic data revealed a long elimination half-life (mean values of 36.1 and 33.8 hours, respectively, for the doses of 0.05 and 0.10 mg/ kg) and mean AUC determinations of 1.5 and 3.1 pg/mL/hr, respectively. Because relatively high doses of 0.05 and O.lOmg/kg/day were given, which will probably be not reached after oral intake of recommended doses of SJW extract preparations, it is not surprising that hypericin caused a considerable phototoxicity in this study. 

Animal studies Early pharmacokinetic studies in mice report that maximum plasma concentrations of hypericin and pseudohypericin were reached at six hours and were maintained for at least eight hours. The aqueous-ethanolic SJW extract used in this study contained 1.0 mg of hypericin (77). 

Pharmacokinetics and cerebrospinal fluid penetration of hypericin were studied after i.v. dose of 2 mg/kg in monkeys (Table 2) (70). Mean peak plasma concentration of hypericin following this dose was 71.7pg/mL (142 pM). Elimination of hypericin from plasma was biexponential, with an average terminal half-life of 26 14 hours. The 2 mg/kg dose in nonhuman primates was sufficient to maintain plasma concentrations above 5.1 pg/mL (10 pM) for up to 12 hours (the in vitro concentration required for growth inhibition of human glioma cell lines is greater than 10 pM). 

In general, the biological evaluation of hypericin in various test models is limited by its poor water solubility. It was shown in in vitro as well as in vivo studies (18,78) that the water solubility of hypericin was remarkably enhanced in the presence of procyanidins or flavonol glycosides of SJW extract. In a recent pharmacokinetic study in rats, it was shown that procyanidin B2 as well as hyperoside increased the oral bioavailability of hypericin by approximately 58% (B2) and 34% (hyperoside) (Fig. 5) (19). Procyanidin B2 and hyperoside had a different influence on the plasma kinetics of hypericin median maximal plasma levels of hypericin were detected after 360 minutes (Cmav 8.6 ng/mL) for B2, and after 150 minutes... 

Butterweck V, Lieflaender-Wulf U, Winterhoff H, Nahrstedt A. Plasma levels of hypericin in presence of procyanidin B2 and hyperoside a pharmacokinetic study in rats. Planta Med 2003 69 189-192. 

Fox E, Murphy RF, McCully CL, Adamson PC. Plasma pharmacokinetics and cerebrospinal fluid penetration of hypericin in nonhuman primates. Cancer Chemother Pharmacol 2001 47 41-44. 

Jacobson JM, Feinman L, Liebes L, et al. Pharmacokinetics, safety, and antiviral effects of hypericin, a derivative of St. John s wort plant, in patients with chronic hepatitis C virus infection. Antimicrob Agents Chemother 2001 45 517-524. 

Kerb R, Brockmoeller J, Staffeldt B, Ploch M, Roots I. Single-dose and steady state pharmacokinetics of hypericin and pseudohypericin. Antimicrob Agents Chemother 1996 40 2087-2093. 

Stock S, Hoelzl J. Pharmacokinetic tests of (14C)-labeled hypericin and pseudohypericin from Hypericum perforatum and serum kinetics of hypericin in man. Planta Med 1991 57 A61. 

St. John s wort contains an enzyme inducer that can reduce the plasma concentrations of drugs that are substrates of CYP3A4, such as indinavir and ciclosporin. However, in eight healthy volunteers aged 24-43 years, St. John s wort 300 mg/day (0.3% hypericin standardized tablet) for 14 days had no effect on the pharmacokinetics of carbamazepine (110). 

Two pharmacokinetic studies have examined the pharmacokinetics of hypericin and pseudohypericin (41,42). Standardized hypericum extract LI 160 (Jarsin 300 , Lichtwer Pharma GmbH, Berlin) was used in both trials. In Part I of the studies, subjects in both trials were administered a single dose of either 300, 900, or 1800 mg of the extract (one, three, or six coated tablets) at 10- to 14-day intervals. Each dose contained 250, 750, or 1500 p.g of hypericin and 526, 1578, or 3156 p,g of pseudohypericin, respectively. The doses were administered on an empty stomach in the morning after a 12-hour fast. Subjects fasted for an additional 2 hours after administration. Multiple plasma levels of hypericin and pseudohypericin were measured for up to 120 hours after administration. In addition, urine samples were collected in the study performed by Kerb and colleagues. After a 4-week washout from Part I, subjects were given one coated tablet containing 300 mg of hypericum extract three times a day (8 am, 1 pm, and 6 pm) before meals for 14 days. Blood samples were obtained over the 2-week dosing period. 

Brockmoller J, Reum T, Bauer S, Kerb R, Hubner WD, Roots I. Hypericin and Pseudohypericin pharmacokinetics and effects on photosensitivity in humans. Pharmacopsychiatry 1997 30(Suppl) 94—101. 

Due to their complex composition the pharmacokinetic assessment of herbal medications generally imposes serious technical and regulatory problems. As the active principle(s) of plant extracts are often not known it is difficult to decide which constituent(s) should actually be studied [218]. In the absence of a well defined therapeutically relevant chemical entity, characteristic constituents of herbal preparations are frequently employed for the purpose of standardization. Correspondingly, pharmacokinetic evaluations of Hypericum extracts have almost exclusively been based on the analysis of the naphthodianthrones hypericin 1 and pseudohypericin 2 which represent typical products of members of the genus Hypericum and are considered to be involved in some of their clinical effects. 

Pharmacokinetic evaluations of hypericin 1 and pseudohypericin 2 in experimental animals are restricted to studies in mice. Following intravenous injection of 17.5 mg/kg of synthetically prepared hypericin peak concentrations of 27.8 pg/ml were measured at 10 min and decreasing values could be followed for a period of 240 h (10 ng/ml). The data were well adjusted to a two-compartment model with a distribution phase (ti/2a) of 2 h and an elimination half life (ti/2(3) of 38.5 h. The volume of... 

Table 3. Pharmacokinetic Parameters of Hypericin 1 and Pseudohypericin 2 After Oral Administration of 900 mg of a Methanolic Hypericum extract to Human Volunteers...

St John s wort modestly increased the clearance of single-dose carbamazepine, but had no effect on multiple-dose carbamazepine pharmacokinetics. Carbamazepine does not appear to significantly affect the pharmacokinetics of hypericin or pseudohypericin (constituents of St John s wort). St John s wort is predicted to reduce the blood levels of phenytoin and phenobar-bital, but this awaits clinical confirmation. 

In a multiple-dose study, St John s wort had no effect on the pharmacokinetics of carbamazepine or its metabolite (carbamazepine-10,ll-epox-ide) in 8 healthy subjects. In this study, subjects took carbamazepine 200 mg increased to 400 mg daily alone for 20 days, then with St John s wort 300 mg (standardised to 0.3% hypericin) three times daily for a further 14 days. In contrast, the AUC of a single 400-mg dose of carbamazepine was reduced by 21% after St John s wort 300 mg was given three times daily for 14 days, and the AUC of the 10,11-epoxide metabolite was increased by 26%. ... 

A placebo-controlled study in healthy subjects taking St John s wort (LI160, Lichtwer Pharma) 300 mg three times daily found that, apart from a modest 25% increase in the AUC of pseudohypericin, cimetidine 1 g daily (in divided doses) did not significantly affect the pharmacokinetics of either the hypericin or pseudohypericin constituents of St John s wort. The available evidence therefore suggests that cimetidine is unlikely to affect the dose requirements of St John s wort. ... 

Brockmoller, T. Reum, S. Bauer, et al. 1997. Hypericin and pseudohypericin Pharmacokinetics and effects on photosensitivity in humans. Pharmacopsychiatry 30(Suppl. 2) 94-101. 

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