Bill J. Gurley

Self-emulsifying drug delivery systems (SEDDS) of coenzyme Q10: formulation development and bioavailability assessment

The goals of our investigations are to develop and characterize self-emulsifying drug delivery systems (SEDDS) of coenzyme Q10 (CoQ10), using polyglycolyzed glycerides (PGG) as emulsifiers and to evaluate their bioavailability in dogs. Solubility of CoQ10 was determined in various oils and surfactants. SEDDS consisted of oil, a surfactant and a cosurfactant. Four types of self-emulsifying formulations were prepared using two oils (Myvacet 9-45 and Captex-200), two emulsifiers (Labrafac CM-10 and Labrasol) and a cosurfactant (lauroglycol). In all the formulations, the level of CoQ10 was fixed at 5.66% w/w of the vehicle. The in vitro self-emulsification properties and droplet size analysis of these formulations upon their addition to water under mild agitation conditions were studied. Pseudo-ternary phase diagrams were constructed identifying the efficient self-emulsification region. From these studies, an optimized formulation was selected and its bioavailability was compared with a powder formulation in dogs. Medium chain oils and Myvacet 9-45 provided higher solubility than long chain oils. Efficient and better self-emulsification processes were observed for the systems containing Labrafac CM-10 than formulations containing Labrasol. Addition of a cosurfactant improved the spontaneity of self-emulsification. From these studies, an optimized formulation consisting of Myvacet 9-45 (40%), Labrasol (50%) and lauroglycol (10%) was selected for its bioavailability assessment. A two-fold increase in the bioavailability was observed for the self-emulsifying system compared to a powder formulation. SEDDS have improved the bioavailability of CoQ10 significantly. The data suggest the potential use of SEDDS to provide an efficient way of improving oral absorption of lipophilic drugs.

Cytochrome P450 phenotypic ratios for predicting herb-drug interactions in humans.

Phytochemical‐mediated modulation of cytochrome P450 (CYP) activity may underlie many herb‐drug interactions. Single‐time point phenotypic metabolic ratios were used to determine whether long‐term supplementation of St Johns wort, garlic oil, Panax ginseng, and Ginkgo biloba affected CYP1A2, CYP2D6, CYP2E1, or CYP3A4 activity.

Clinical assessment of effects of botanical supplementation on cytochrome P450 phenotypes in the elderly: St John's wort, garlic oil, Panax ginseng and Ginkgo biloba.

ObjectivesElderly patients are more likely to ingest prescription medications concurrently with botanical supplements, and may therefore be vulnerable to herb-drug interactions. Phytochemical-mediated modulation of cytochrome P450 (CYP) activity may underlie many herb-drug interactions. Some evidence suggests that CYP activity may decrease in the elderly. If so, herb-mediated changes in CYP activity may take on greater clinical relevance in this population. In this study, single timepoint, phenotypic metabolic ratios were used to determine whether long-term supplementation of St John’s wort, garlic oil, Panax ginseng, and Ginkgo biloba affected CYP1A2, CYP2D6, CYP2E1 or CYP3A4 activity in elderly subjects.MethodsTwelve healthy volunteers between the ages of 60 and 76 years (mean age 67 years) were randomly assigned to receive each botanical supplement for 28 days followed by a 30-day washout period. Probe drug cocktails of midazolam, caffeine, chlorzoxazone and debrisoquine were administered before and at the end of supplementation. Pre- and post-supplementation phenotypic ratios were determined for CYP3A4, CYP1A2, CYP2E1 and CYP2D6 using 1-hydroxymidazolam/midazolam serum ratios (1-hour), paraxanthine/caffeine serum ratios (6-hour), 6-hydroxychlorzoxazone/chlorzoxazone serum ratios (2-hour) and debrisoquine urinary recovery ratios (8-hour), respectively. The content of purported ‘active’ phytochemicals was determined for each supplement.ResultsComparisons of pre- and post-St John’s wort phenotypic ratios revealed significant induction of CYP3A4 (≈140%) and CYP2E1 activity (≈28%). Garlic oil inhibited CYP2E1 activity by approximately 22%. P. ginseng inhibition of CYP2D6 was statistically significant, but the magnitude of the effect (≈7%) did not appear to be clinically relevant. None of the supplements tested in this study appeared to affect CYP1A2 activity.ConclusionsElderly subjects, like their younger counterparts, are susceptible to herb-mediated changes in CYP activity, especially those involving St John’s wort. Pharmacokinetic herb-drug interactions stemming from alterations in CYP activity may adversely affect drug efficacy and/or toxicity. When compared with earlier studies that employed young subjects, the data suggest that some age-related changes in CYP responsivity to botanical supplementation may exist. Concomitant ingestion of botanical supplements with prescription medications, therefore, should be strongly discouraged in the elderly.

In vivo assessment of botanical supplementation on human cytochrome P450 phenotypes: Citrus aurantium, Echinacea purpurea, milk thistle, and saw palmetto

Phytochemical‐mediated modulation of cytochrome P450 (CYP) activity may underlie many herb‐drug interactions. Single‐time point phenotypic metabolic ratios were used to determine whether long‐term supplementation of Citrus aurantium, Echinacea purpurea, milk thistle (Silybum marianum), or saw palmetto (Serenoa repens) extracts affected CYP1A2, CYP2D6, CYP2E1, or CYP3A4 activity.

Drug Interaction between St. John's Wort and Cyclosporine

OBJECTIVE: To report a probable drug interaction between the herbal dietary supplement St. Johns wort and cyclosporine. CASE REPORT: A 29-year-old white woman who received a cadaveric kidney and pancreas transplant, with stable organ function and stable cyclosporine concentrations began self-medicating with St. Johns wort. After taking St. Johns wort supplements for four to eight weeks, her cyclosporine concentrations became subtherapeutic; this was associated with organ rejection. Four weeks after stopping St. Johns wort, her cyclosporine concentrations again became therapeutic. Subsequent to this rejection episode, she has developed chronic rejection and now has returned to dialysis. DISCUSSION: St. Johns wort is suspected to be a significant inducer of CYP3A4 isoenzyme activity and of P-glycoprotein (P-gp) expression, both of which are important in the metabolism and absorption of cyclosporine. Cyclosporine exhibits a relatively small therapeutic window and is sensitive to medications that can modulate the CYP3A4 isoenzyme and P-gp in both the liver and small intestines. CONCLUSIONS: Patients taking St. Johns wort concomitant with other prescription medications whose absorption and metabolism are mediated by the CYP3A4 isoenzyme and P-gp require close monitoring. Patient medication histories should include inquiries into the use of herbal dietary supplements.

Clinical assessment of CYP2D6-mediated herb–drug interactions in humans: Effects of milk thistle, black cohosh, goldenseal, kava kava, St. John's wort, and Echinacea

Cytochrome P450 2D6 (CYP2D6), an important CYP isoform with regard to drug-drug interactions, accounts for the metabolism of approximately 30% of all medications. To date, few studies have assessed the effects of botanical supplementation on human CYP2D6 activity in vivo. Six botanical extracts were evaluated in three separate studies (two extracts per study), each incorporating 16 healthy volunteers (eight females). Subjects were randomized to receive a standardized botanical extract for 14 days on separate occasions. A 30-day washout period was interposed between each supplementation phase. In study 1, subjects received milk thistle (Silybum marianum) and black cohosh (Cimicifuga racemosa). In study 2, kava kava (Piper methysticum) and goldenseal (Hydrastis canadensis) extracts were administered, and in study 3 subjects received St. Johns wort (Hypericum perforatum) and Echinacea (Echinacea purpurea). The CYP2D6 substrate, debrisoquine (5 mg), was administered before and at the end of supplementation. Pre- and post-supplementation phenotypic trait measurements were determined for CYP2D6 using 8-h debrisoquine urinary recovery ratios (DURR). Comparisons of pre- and post-supplementation DURR revealed significant inhibition (approximately 50%) of CYP2D6 activity for goldenseal, but not for the other extracts. Accordingly, adverse herb-drug interactions may result with concomitant ingestion of goldenseal supplements and drugs that are CYP2D6 substrates.

Pharmacokinetics and cardiovascular effects of ma-huang (Ephedra sinica) in normotensive adults.

The purpose of this study was to evaluate heart rate and blood pressure responses to a commercially available source of ma‐haung, a natural source of the sympathomimetic substance, ephedrine, and to evaluate the pharmacokinetic properties of the product in normotensive, healthy adults. On day 1, twelve study participants were monitored with an ambulatory blood pressure device between hours 7 and 20. On day 2, they ingested four capsules of powdered ma‐huang at hours 8 and 17 while again wearing the monitor between hours 7 and 20. Serial plasma samples were obtained and concentrations of ephedrine were analyzed by high‐performance liquid chromatography. Pharmacokinetic parameters of ephedrine were determined from plasma concentration‐time profiles. The ephedrine alkaloid content of each capsule was also determined by high‐performance liquid chromatography. Six participants experienced a statistically significant increase in heart rate, but the effects on blood pressure were variable. The half‐life, volume of distribution, clearance, and maximum concentration in plasma of ephedrine in the ma‐huang product were similar to values previously reported for a 20‐mg, immediate‐release ephedrine tablet. Values for the absorption rate were considerably lower and time to reach maximum concentration was longer for the capsules, compared with the standard tablet. Variability in alkaloid content of ephedrine was low and yielded a mean dose of ephedrine at 19.4 mg; pseudoephedrine at 4.9 mg; and methylephedrine at 1.2 mg for a four‐capsule dose. In summary, ma‐haung had variable effects on blood pressure and increased heart rate in healthy, normotensive adults. Pharmacokinetic parameters for ephedrine were in agreement with those previously reported; however, the absorption rate was much slower after ingestion of ma‐huang.

Herbal supplements: a potential for drug interactions in transplant recipients.

Background. Herbal dietary supplements represent a potential and possibly an overlooked cause for drug interactions in transplant recipients. Methods. Two patients are reported which suggest that St. John’s Wort (SJW) may induce cytochrome P-450 3A4 activity and/or P-glycoprotein expression. Both of these mechanisms are significantly involved in the metabolism and absorption of cyclosporine (CSA) and other immunosuppressants. Results. After two renal transplant recipients started self-medicating with SJW, their CSA concentrations were consistently documented to be subtherapeutic. While on SJW, one patient developed acute graft rejection due to low CSA concentrations. In both patients, termination of SJW returned their CSA concentrations to therapeutic values. Conclusions. Patients taking SJW concomitantly with CSA or other medications whose absorption and metabolism are mediated by cytochrome P-450 and/or P-glycoprotein should require close monitoring. Potential herb-prescription drug interactions are not just limited to SJW. Inquiries regarding the usage of herbal supplements should be an integral component of a transplant recipient’s medication history.

Effect of milk thistle (Silybum marianum) and black cohosh (Cimicifuga racemosa) supplementation on digoxin pharmacokinetics in humans

Phytochemical-mediated modulation of P-glycoprotein (P-gp) and other drug transporters may underlie many herb-drug interactions. Serial serum concentration-time profiles of the P-gp substrate, digoxin, were used to determine whether supplementation with milk thistle or black cohosh modified P-gp activity in vivo. Sixteen healthy volunteers were randomly assigned to receive a standardized milk thistle (900 mg daily) or black cohosh (40 mg daily) supplement for 14 days, followed by a 30-day washout period. Subjects were also randomized to receive rifampin (600 mg daily, 7 days) and clarithromycin (1000 mg daily, 7 days) as positive controls for P-gp induction and inhibition, respectively. Digoxin (Lanoxicaps, 0.4 mg) was administered orally before and at the end of each supplementation and control period. Serial digoxin serum concentrations were obtained over 24 h and analyzed by chemiluminescent immunoassay. Comparisons of area under the serum concentration time curves from 0 to 3 h (AUC(0–3)), AUC(0–24), Cmax, apparent oral clearance of digoxin (CL/F), and elimination half-life were used to assess the effects of milk thistle, black cohosh, rifampin, and clarithromycin on digoxin pharmacokinetics. Rifampin produced significant reductions (p < 0.01) in AUC(0–3), AUC(0–24), and Cmax, whereas clarithromycin increased these parameters significantly (p < 0.01). Significant changes in digoxin half-life and CL/F were also observed with clarithromycin. No statistically significant effects on digoxin pharmacokinetics were observed following supplementation with either milk thistle or black cohosh, although digoxin AUC(0–3) and AUC(0–24) approached significance (p = 0.06) following milk thistle administration. When compared with rifampin and clarithromycin, supplementation with these specific formulations of milk thistle or black cohosh did not appear to affect digoxin pharmacokinetics, suggesting that these supplements are not potent modulators of P-gp in vivo.

Gauging the clinical significance of P-glycoprotein-mediated herb-drug interactions: Comparative effects of St. John's wort, Echinacea, clarithromycin, and rifampin on digoxin pharmacokinetics

Concomitant administration of botanical supplements with drugs that are P-glycoprotein (P-gp) substrates may produce clinically significant herb-drug interactions. This study evaluated the effects of St. Johns wort and Echinacea on the pharmacokinetics of digoxin, a recognized P-gp substrate. Eighteen healthy volunteers were randomly assigned to receive a standardized St. Johns wort (300 mg three times daily) or Echinacea (267 mg three times daily) supplement for 14 days, followed by a 30-day washout period. Subjects were also randomized to receive rifampin (300 mg twice daily, 7 days) and clarithromycin (500 mg twice daily, 7 days) as positive controls for P-gp induction and inhibition, respectively. Digoxin (Lanoxin 0.25 mg) was administered orally before and after each supplementation and control period. Serial digoxin plasma concentrations were obtained over 24 h and analyzed by chemiluminescent immunoassay. Comparisons of area under the curve (AUC)((0-3)), AUC((0-24)), elimination half-life, and maximum serum concentration were used to assess the effects of St. Johns wort, Echinacea, rifampin, and clarithromycin on digoxin disposition. St. Johns wort and rifampin both produced significant reductions (p < 0.05) in AUC((0-3)), AUC((0-24)), and C(max), while clarithromycin increased these parameters significantly (p < 0.05). Echinacea supplementation did not affect digoxin pharmacokinetics. Clinically significant P-gp-mediated herb-drug interactions are more likely to occur with St. Johns wort than with Echinacea.