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Basic pharmacology of buprenorphine
European Journal of Pain Supplements 1 (2007) 69–73 www.EuropeanJournalPain.com
Basic pharmacology of buprenorphine Michiteru Ohtani * Department of Hospital Pharmacy, Tokyo Teishin Hospital, 2-14-23 Fujimi, Chiyoda-ku, Tokyo, Japan
Abstract Buprenorphine is a derivative of the morphine alkaloid thebaine. The plasma elimination half-life of buprenorphine is three times longer than that of the active metabolite, norbuprenorphine. Although the elimination of norbuprenorphine from the body is more rapid than that of buprenorphine, the plasma concentration of norbuprenorphine was observed to exceed that of buprenorphine with chronic administration of buprenorphine. This plasma level of norbuprenorphine is based on the proportional increase in norbuprenorphine-glucuronide observed after one enterohepatic circulation of buprenorphine due to the first-pass metabolism. When buprenorphine and norbuprenorphine were administered intraventricularly, the analgesic effect of norbuprenorphine was approximately one-fourth that of buprenorphine. After intravenous administration of buprenorphine or norbuprenorphine in rats, the analgesic effect of norbuprenorphine was approximately 1/50th that of buprenorphine. The remarkably weak analgesic effect of norbuprenorphine after intravenous administration may be due to the low permeability of norbuprenorphine into the brain. Therefore, the plasma concentration of norbuprenorphine with chronic administration of buprenorphine has little analgesic effect. The most dangerous side effect of opioid therapy is respiratory depression. In our study of the respiratory effects after intravenous infusion in rats, norbuprenorphine was ten times more potent than the parent drug. However, it is possible that the plasma levels of norbuprenorphine with chronic administration of buprenorphine are not sufficiently high to depress respiratory function. Overall, buprenorphine is a safe and highly effective analgesic opioid for the treatment of chronic pain. © 2007 European Federation of Chapters of the International Association for the Study of Pain. Published by Elsevier Ltd. All rights reserved. Keywords: Buprenorphine; Norbuprenorphine; Pharmacokinetics; Pharmacology
1. Introduction In the 19th century, buprenorphine was unfortunately given the label “partial agonist”. Buprenophine is a semisynthetic opioid derived from thebaine. The chemical structure of buprenorphine resembles that of morphine, but it contains N-cyclopropylmethyl. The N-cyclopropylmethyl analogues of opioids are, in many cases, particularly potent antagonists of morphine. A bell-shaped dose-response curve has been reported (Budd, 1981). However, in the clinical setting for the treatment of pain, a bell-shaped doseresponse curve has not been demonstrated and buprenorphine acts as a pure µ-opioid agonist. The duraction of
* Correspondence to: Michiteru Ohtani, Department of Hospital Pharmacy, Tokyo Teishin Hospital, 2-14-23 Fujimi, Chiyoda-ku, Tokyo 1028798, Japan. E-mail address: [email protected]
action of buprenorphine is up to two-fold that of morphine and it is approximately 30-fold more potent (Cowan et al., 1977a). The therapeutic index of buprenorphine is four-fold greater than that of morphine, indicating a wider safety margin (Cowan et al., 1977b). Buprenorphine undergoes extensive first-pass effect metabolism in the liver and gut. It was therefore marketed only as a parenteral injection and sublingual tablet for a long time. Since these formulations were not continuousrelease preparations, the clinical use of buprenorphine for the treatment of chronic pain was limited. The reason why the clinical use of buprenorphine for the treatment of pain was limited was not only confusion about the term “partial agonist-antagonist” or its first-pass effects but also the lack of information on the pharmacokinetics and pharmacology of buprenorphine and its active metabolite. The purpose of this review is to provide clinicians and researchers with information on the pharmacokinetics and pharmacology of buprenorphine.
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2. Pharmacokinetic study 2.1. Pharmacokinetic parameters The plasma concentration of buprenorphine declines biexponentially after intravenous administration of 0.6 mg/kg to rats (Fig. 1) (Ohtani et al., 1994). Although norbuprenorphine was found in the plasma for up to 2 h after the administration of buprenorphine, its concentration was within the range of 0.1 ng/mL to 3.5 ng/mL. The mean t1/2 , CLtot , Vdss , and MRT values for buprenorphine at the 0.6 mg/kg dose were 2.8 h, 23.3 mL/min/kg, 4.2 L/kg, and 3.0 h, respectively (Ohtani et al., 1994). These values were similar to those at the 0.06 mg/kg dose. The mean terminal half-life following a single dose of 1.2 mg iv in humans was reported to be 3.2 h (Ohtani et al., 1994). Buprenorphine clearance following intravenous administration was found to be approximately 80 L/h in the clinical setting for the treatment of pain (Kuhlman, 1996). These values from human studies are in agreement with our results in rats (Ohtani et al., 1994). Following the intravenous administration of norbuprenorphine 0.6 mg in rats, the plasma concentration also declined biexponentially (Fig. 1). The mean values of t1/2 , CLtot , Vdss , and MRT for norbuprenorphine were 0.9 h, 35.0 mL/min/kg, 2.0 L/kg, and 1.3 h, respectively (Ohtani et al., 1994). The plasma elimination half-life of buprenorphine was three-fold longer than that of the active metabolite, norbuprenorphine (Ohtani et al., 1994). 2.2. Biliary and urinary excretion and enterohepatic circulation Buprenorphine is primarily metabolized to buprenorphine-glucuronide and partly to norbuprenorphine, with subsequent conversion to norbuprenorphine-glucuronide. Consequently, these conjugated metabolites are mostly excreted in bile (Ohtani et al., 1994) Independent of species, well over one-half of administered buprenorphine is elimi-
Fig 1. Plasma concentration–time profiles of buprenorphine (BN) and nor-BN (NBN) after intravenous administration to rats.
Fig 2. Cumulative biliary excretion of buprenorphine (BN) and nor-BN (NBN) in recipient rats after intravenous administration of BN to donor rats.
nated in the faeces (Ohtani et al., 1994). The mean excretion ratio of buprenorphine-glucuronide and norbuprenorphineglucuronide in the bile after administration of buprenorphine 0.6 mg/kg iv were approximately 75% and 19%, respectively, and that of unchanged buprenorphine and norbuprenorphine was only less than 1% (Ohtani et al., 1994) In contrast, the urinary excretion ratio of norbuprenorphineglucuronide was only 3.2% and that of buprenorphine and buprenorphine-glucuronide was less than 1% (Ohtani et al., 1994) The biliary and urinary excretion ratios of norbuprenorphine-glucuronide and unchanged norbuprenorphine after administration of norbuprenorphine were 85% and 0.1%, and 9.1% and 1.9%, respectively (Ohtani et al., 1994). The enterohepatic circulation of buprenorphine was confirmed in “linked-rat model” experiments. During a 24-h period, 25% of the dose given to the donor rats was found in the bile of the recipient rats as buprenorphineglucuronide, and 59% was found as norbuprenorphineglucuronide (Fig. 2) (Ohtani et al., 1994). The excretion ratio of norbuprenorphine-glucuronide was approximately twice that of buprenorphine-glucuronide. These results are markedly different from the results of the biliary excretion experiments in bile-fistula rats (Ohtani et al., 1994). Therefore, we consider that the difference in excretion pattern may result from the first-pass effects during enterohepatic circulation (Ohtani et al., 1994). Although the elimination of norbuprenorphine from the body was more rapid than that of buprenorphine, the mean plasma concentration of norbuprenorphine after 8-mg sublingual administration of buprenorphine was frequently equal to or higher than that of buprenorphine (Kulhman et al., 1998). This plasma concentration of norbuprenorphine was based on the increase in the proportion of norbuprenorphine-glucuronide observed after the enterohepatic circulation of buprenorphine due to first-pass metabolism. Pontani et al. (1985) discussed the reappearance of buprenorphine conjugates in the bile and hypothesized that buprenorphine conjugates undergo hydrosis, probably via the action of gastrointestinal microorganisms. We also found in our preliminary study that
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nearly 100% of buprenorphine and norbuprenorphine was liberated from the bile within 5 h when a bile sample containing conjugated buprenorphine was incubated with β-glucuronidase at 37°C (Ohtani et al., 1993) From these findings, it appears that buprenorphine-glucuronide and norbuprenorphine-glucuronide excreted in the bile may be absorbed after the return of the parent drugs, buprenorphine and norbuprenorphine, to the intestinal tract. Due to the extensive first-pass effect in the gut lining and liver, the systemic bioavailability of buprenorphine in humans following oral administration is approximately 10% (Robinson et al., 1992). 2.3. Metabolism Two metabolic pathways are well documented, that is, N-dealkylation by CYP3A4 and glucuronidation, leading to the three major metabolites of buprenorphine: buprenorphine-3-glucuronide; N-dealkylbupurenorphine, which is its only active metabolite; and norbuprenorphine-3glucuronide. The in vitro metabolic rate of glucuronidation and N-dealkylation of the 9000-g supernatant fraction in the liver and small intestine are shown in Table 1. There was no significant difference between the mean glucuronidation rate of buprenorphine and norbuprenorphine in the liver and small intestine. On the other hand, the N-dealkylation reaction was 100-fold greater in the liver than in the small intestine (Ohtani et al., 1993). The contents of cytochrome P-450 after repeated administration of doses of 0.03 to 0.6 mg/kg decreased significantly as compared with those in control rats given saline (Ohtani et al., 1994). On the other hand, there was no decrease with the 0.003 mg/kg dose as compared with control rats (Fig. 3) (Ohtani et al., 1994). This reduction in the contents of cytochrome P-450 is due to the cyclopropylmethyl group in the buprenorphine structure. The oxidation rate of buprenorphine in the liver in rats pretreated with buprenorphine 0.6 mg/kg was decreased to 20% of that in controls (Ohtani et al., 1994). In contrast, there was no decrease after the administration of 0.003 mg/kg as compared with the saline controls. There was no change in AST and ALT activities in the plasma at any dose in pretreated rats (Ohtani et al., 1993). Therefore, the most commonly used dosage for the treatment of pain has little effect on the oxidation rate. In vitro studies with human liver microsomes found
Table 1 In vitro metabolic rate for glucuronidation of buprenorphine (BN) and norbuprenorphine (NBN) and N -dealkylation for BN (values in ng/g/min) Tissue
Liver Small intestine
Glucuronidation
N -dealkylation
BN
NBN
BN
706 ± 122 572 ± 147
1340 ± 335 1635 ± 158
525 ± 175 6±0
Each value represents the mean ± SD of tree thrials.
Fig 3. Change in hepatic cytochrome P-450 contents during repeated dosing with buprenorphine.
that buprenorphine is a strong inhibitor of CYP3A4 and CYP2D6, and it also weakly inhibited CYP1A2, CYP2B6, CYP2C19, CYP2C8, CYP2C9, CYP2E1, and CYP2A6 (Ohtani et al., 1993). However, at the therapeutic concentration of buprenorphine, it would not be expected to cause clinically significant interactions with other drugs metabolized by CYP (Umehara et al., 2002).
3. Pharmacology 3.1. Analgesic effects Buprenorphine has a bell-shaped dose-response curve for antinociception and catalepsy (Zhang et al., 2003). However, the study by Zhang et al.(2003) was performed using high doses of buprenorphine, and the normal therapeutic dose range does not result in a bell-shaped dose-response curve. Instead, buprenorphine has been observed to exhibit a linear dose-response relationship in terms of analgesic effects. We compared the analgesic effects of buprenorphine and norbuprenorphine based on a pharmacokineticpharmacodynamic model (Ohtani et al., 1995). The change in latency time after intraventricular administration of buprenorphine or norbuprenorphine to rats is shown Fig. 4. After intraventricular injection of norbuprenorphine, the intrinsic analgesic activity was approximately 25% more potent than that of buprenorphine (Ohtani et al., 1995). The analgesic effects of norbuprenorphine after intravenous administration were approximately 2% of that of buprenorphine (Ohtani et al., 1995). To compare the lipophilicity between buprenorphine and norbuprenorphine, the n-octanol/ water partition coefficient of norbuprenorphine was 10% of that of buprenorphine (Ohtani et al., 1995). The brainto-plasma ratio of buprenorphine ranged from 1.1 to 3.3 (Ohtani et al., 1995). In contrast, the brain distribution of norbuprenorphine after administration was greatly reduced when compared with that of buprenorphine, and the brain-to-plasma ratio of norbuprenorphine was less than 0.1
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Fig 4. Change in latency time after intraventriclar injection of buprenorphine (BN) or nor-BN (NBN) to rats.
(Ohtani et al., 1995). Therefore, the weak analgesic effects of norbuprenorphine after intravenous administration may be due not only to the low permeability of norbuprenorphine into the brain, consistent with its low n-octanol/water partition coefficient, but also to its intrinsically weak analgesic effects. Therefore, the plasma concentration of norbuprenorphine with chronic administration of buprenorphine has little analgesic effect. Buprenorphine produces analgesic effects at a low plasma concentration. In contrast, norbuprenorphine does not produce analgesic effects within the therapeutic range. Therefore, the plasma concentration of norbuprenorphine with chronic administration of buprenorphine has little analgesic effect (Broude et al., 1974).
of 0.008 to 3 mg/kg (Ohtani et al., 1997). In contrast, the respiratory rate after an intravenous bolus administration of norbuprenorphine decreased in a dose-dependent fashion within the dose range of 1 to 3 mg/kg (Ohtani et al., 1997). The minimum respiratory rate was observed 15 min after norbuprenorphine administration (Ohtani et al., 1997). As shown in Fig. 5, the reduction in respiratory rate and the increase in pCO2 after buprenorphine administration was observed only with a high infusion rate. In contrast, norbuprenorphine decreased the respiratory rate and increased pCO2 dose dependently (Ohtani et al., 1997). The depression of the respiratory rate by norbuprenorphine was approximately 10-fold greater than that by buprenorphine (Ohtani et al., 1997). The respiratory rate depression induced by norbuprenorphine was immediately recovered after administration of β-FNA, a selective opioid µ-receptor (Ohtani et al., 1997). However, the respiratory depression was not improved by a selective δ-receptor antagonist, ICI 174864 (Ohtani et al., 1997). Therefore, we suggest that the depression of respiratory function is mediated by the µ-receptor. As shown in Fig. 6, after buprenorphine administration, analgesic effects are produced at a low plasma buprenor-
3.2. Respiratory depression The most dangerous complication of opioid therapy is respiratory depression. The lowest incidence of respiratory depression was found with buprenorphine. Based on the results of recent clinical and animal studies, the lack of respiratory depression with buprenorphine has clear clinical advantages over other classic µ]-agonist opioids (Dahan et al., 2005). After intravenous bolus administration of buprenorphine, no effects were noted over the dose range
Fig 6. Relationships between plasma concentration of buprenorphine (BN) or nor-BN (NBN) and analgesic effects or respiratory depression.
Fig 5. Relationships between infusion rate of buprenorphine (BN) or nor-BN (NBN) and respiratory rate or arterial pCO2.
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phine concentration, whereas respiratory depression is not induced even at a 1000-fold higher concentration. In contrast, to obtain analgesic effects with norbuprenorphine comparable to those with buprenorphine, it is necessary to maintain the norbuprenorphine concentration at a 50-fold higher value, at which point the concentration that induces respiratory depression is close to that producing analgesic effects (Ohtani et al., 1997). However, it is possible that the plasma level of norbuprenorphine observed with chronic administration of buprenorphine is not sufficiently high to cause depression of the respiratory rate (Ohtani et al., 1995). Recently, Dahan et al.(2005a) have shown that the ceiling for the respiratory effect occurs at a much lower dose than the ceiling for analgesic effects, which indicates the relative safety of buprenorphine combined with its ability to produce effective analgesia. Buprenorphine has a high affinity for and slow dissociation from µ-opioid receptors. Because of this, a single bolus administration of naloxone leads to partial, short-lived reversal of buprenorphineinduced respiratory (Dahan et al., 2005a). Thus, reversal of buprenorphine-induced respiratory depression requires a continuous infusion of naloxone (Dorp et al., 2006).
4. Conclusion In conclusion, the tissue distribution of norbuprenorphine has been shown to be less than that of buprenorphine, and the elimination of norbuprenorphine is more rapid than that of the parent drug. Buprenorphine and norbuprenorphine undergo extensive enterohepatic circulation. The plasma level of norbuprenorphine with chronic administration of buprenorphine was based on the increase in the proportion of norbuprenorphine-glucuronide observed after the enterohepatic circulation of buprenorphine due to first-pass metabolism. The amount of cytochrome P-450 and the oxidation rate of buprenorphine in the hepatic microsome fraction after repeated administration of doses ranging from 0.03 to 0.6 mg/kg decreased significantly as compared with those in control rats given saline (Ohtani et al., 1994). In contrast, there was no decrease after the administration of 0.003 mg/kg as compared with the saline controls (Ohtani et al., 1993). Therefore, the most commonly used dosage for the treatment of pain has little effect on the oxidation rate. The analgesic effects of buprenorphine are produced at a low plasma concentration, whereas respiratory depression is not induced even at a 1000-fold higher concentration. In contrast, the plasma concentration of norbuprenorphine with chronic administration of buprenorphine has little analgesic effect and respiratory depression. Overall, buprenorphine displays more favorable analgesic and respiratory pharmacology compared with other
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classic µ-agonists, and it is safe and highly effective in the treatment of pain. In particular, the transdermal patch formulation of buprenorphine is user-friendly, and patient compliance has been shown to increase and the quality of life of patients to improve with its use (Bohme., 2002). To ensure that buprenorphine preparations are used appropriately, it is necessary to enlighten clinicians who prescribe them for the treatment of pain.
References Bohemn K. Buprenorphine in a transdermal therapeutic system – a new option. Clin Rheumatol 2002;Suppl 1:S13-16. Budd K. High dose buprenorphine for postoperative analgesia. Anaesthesia 1981;36:900–903. Cowan A, Lewis JW. Agonist and antagonist properties of buprenorphine, a new antinociceptive agent. Br J Pharmacol 1977;60:537–545. Cowan A, Doxey JC, Harry EJR. The animal pharmacology of buprenorphine, an oripavine analgesic agent. Br J Pharmacol 1977;60:547–554. Dahan A, Yassen A, Bijl H, Romberg R, Sarton L, Olofsen E, Danhof M. Comparison of the respiratory effects of intravenous buprenorphine and fentanyl in humana and rats. Br J Anaesthesiol 2005a;94:825– 834. Dorp EV, Yassen A, Sarton E, Romberg R, Olofsen E, Teppema L, Dahan A. Naloxone reversal of buprenorphine-induced respiratory depression. Anesthesiology 2006;10:551-557. Harris D, Robinson JR. Drug delivery via the mucous membranes of the oral cavity. J Pharm Sci 1992;81:1–10. Kuhlman JJ, Lalani S, Magluilo J. Human pharmacokinetics of intravenous, sublingual, and buccal buprenorphine. J Anal Toxicol 1996a;20:369–378. Kuhlman JJ. Levine B, Johnson RE, Fudala PJ, Cone JE. Relationship of plasma buprenorphine and norbuprenorphine to withdrawal symptoms during dose induction, maintenance and withdrawal from sublingual buprenorphine. Addiction 1998;93:549–559. Lewis JW. Narcotic antagonists. In: Broude, MC, Harris, LS, May EL, Smith JP, Villarreal JE (Eds.), Advances in Biochemical Psychopharmacology. New York: Raven Press, 1974; pp. 123–135. Ohtani M, Kotaki H, Santa T, Sawada Y, Iga T. Effect of repeated administration of buprenorphine, an opioid analgesic, on its oxidative metabolism in rats. Yakubutu Doutai 1993;8:1219–1227. Ohtani M, Kotaki H, Sawada Y, Iga T. Comparative analysis of buprenorphine- and norbuprenorphine-induced analgesic effects based on pharmacokinetic-pharmacodynamic modeling. J Pharmacol Exp Ther 1995;272:505–510. Ohtani M, Kotaki H, Uchino K, Sawada Y, Iga T. Pharmacokinetic analysis of enterohepatic circulation of buprenorphine and its active metabolite, norbuprenorphine, in rats. Drug Metabol Disp 1994;22:2– 7. Ohtani M, Kotaki H, Nishitateno K, Sawada Y, Iga T. Kinetics of respiratory depression in rats induced by buprenorphine and its metabolite, norbuprenorphine. J Pharmacol Exp Ther 1997;281:428–433. Pontani RB,Vadlamani NL, MisraL. Disposition in the rats of buprenorphine administered parenterally and as a subcutaneous implant. Xenobiotica 1985;15:287–297. Umehara K, Shimokawa Y, Miyamoto M. Inhibition of human drug metabolizing cytochrome P450 by buprenorphine. Biol Pharm Bull 2002;25:682–685. Zhang W, Ramamoorthy Y, Tyndale RF, Sellers EM. Interaction of buprenorphine and its metabolite norbuprenorphine with cytochromes P450 in vitro. Drug Metabol Disp 2003;31:768–772.
Basic pharmacology of buprenorphine Michiteru Ohtani * Department of Hospital Pharmacy, Tokyo Teishin Hospital, 2-14-23 Fujimi, Chiyoda-ku, Tokyo, Japan
Abstract Buprenorphine is a derivative of the morphine alkaloid thebaine. The plasma elimination half-life of buprenorphine is three times longer than that of the active metabolite, norbuprenorphine. Although the elimination of norbuprenorphine from the body is more rapid than that of buprenorphine, the plasma concentration of norbuprenorphine was observed to exceed that of buprenorphine with chronic administration of buprenorphine. This plasma level of norbuprenorphine is based on the proportional increase in norbuprenorphine-glucuronide observed after one enterohepatic circulation of buprenorphine due to the first-pass metabolism. When buprenorphine and norbuprenorphine were administered intraventricularly, the analgesic effect of norbuprenorphine was approximately one-fourth that of buprenorphine. After intravenous administration of buprenorphine or norbuprenorphine in rats, the analgesic effect of norbuprenorphine was approximately 1/50th that of buprenorphine. The remarkably weak analgesic effect of norbuprenorphine after intravenous administration may be due to the low permeability of norbuprenorphine into the brain. Therefore, the plasma concentration of norbuprenorphine with chronic administration of buprenorphine has little analgesic effect. The most dangerous side effect of opioid therapy is respiratory depression. In our study of the respiratory effects after intravenous infusion in rats, norbuprenorphine was ten times more potent than the parent drug. However, it is possible that the plasma levels of norbuprenorphine with chronic administration of buprenorphine are not sufficiently high to depress respiratory function. Overall, buprenorphine is a safe and highly effective analgesic opioid for the treatment of chronic pain. © 2007 European Federation of Chapters of the International Association for the Study of Pain. Published by Elsevier Ltd. All rights reserved. Keywords: Buprenorphine; Norbuprenorphine; Pharmacokinetics; Pharmacology
1. Introduction In the 19th century, buprenorphine was unfortunately given the label “partial agonist”. Buprenophine is a semisynthetic opioid derived from thebaine. The chemical structure of buprenorphine resembles that of morphine, but it contains N-cyclopropylmethyl. The N-cyclopropylmethyl analogues of opioids are, in many cases, particularly potent antagonists of morphine. A bell-shaped dose-response curve has been reported (Budd, 1981). However, in the clinical setting for the treatment of pain, a bell-shaped doseresponse curve has not been demonstrated and buprenorphine acts as a pure µ-opioid agonist. The duraction of
* Correspondence to: Michiteru Ohtani, Department of Hospital Pharmacy, Tokyo Teishin Hospital, 2-14-23 Fujimi, Chiyoda-ku, Tokyo 1028798, Japan. E-mail address: [email protected]
action of buprenorphine is up to two-fold that of morphine and it is approximately 30-fold more potent (Cowan et al., 1977a). The therapeutic index of buprenorphine is four-fold greater than that of morphine, indicating a wider safety margin (Cowan et al., 1977b). Buprenorphine undergoes extensive first-pass effect metabolism in the liver and gut. It was therefore marketed only as a parenteral injection and sublingual tablet for a long time. Since these formulations were not continuousrelease preparations, the clinical use of buprenorphine for the treatment of chronic pain was limited. The reason why the clinical use of buprenorphine for the treatment of pain was limited was not only confusion about the term “partial agonist-antagonist” or its first-pass effects but also the lack of information on the pharmacokinetics and pharmacology of buprenorphine and its active metabolite. The purpose of this review is to provide clinicians and researchers with information on the pharmacokinetics and pharmacology of buprenorphine.
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2. Pharmacokinetic study 2.1. Pharmacokinetic parameters The plasma concentration of buprenorphine declines biexponentially after intravenous administration of 0.6 mg/kg to rats (Fig. 1) (Ohtani et al., 1994). Although norbuprenorphine was found in the plasma for up to 2 h after the administration of buprenorphine, its concentration was within the range of 0.1 ng/mL to 3.5 ng/mL. The mean t1/2 , CLtot , Vdss , and MRT values for buprenorphine at the 0.6 mg/kg dose were 2.8 h, 23.3 mL/min/kg, 4.2 L/kg, and 3.0 h, respectively (Ohtani et al., 1994). These values were similar to those at the 0.06 mg/kg dose. The mean terminal half-life following a single dose of 1.2 mg iv in humans was reported to be 3.2 h (Ohtani et al., 1994). Buprenorphine clearance following intravenous administration was found to be approximately 80 L/h in the clinical setting for the treatment of pain (Kuhlman, 1996). These values from human studies are in agreement with our results in rats (Ohtani et al., 1994). Following the intravenous administration of norbuprenorphine 0.6 mg in rats, the plasma concentration also declined biexponentially (Fig. 1). The mean values of t1/2 , CLtot , Vdss , and MRT for norbuprenorphine were 0.9 h, 35.0 mL/min/kg, 2.0 L/kg, and 1.3 h, respectively (Ohtani et al., 1994). The plasma elimination half-life of buprenorphine was three-fold longer than that of the active metabolite, norbuprenorphine (Ohtani et al., 1994). 2.2. Biliary and urinary excretion and enterohepatic circulation Buprenorphine is primarily metabolized to buprenorphine-glucuronide and partly to norbuprenorphine, with subsequent conversion to norbuprenorphine-glucuronide. Consequently, these conjugated metabolites are mostly excreted in bile (Ohtani et al., 1994) Independent of species, well over one-half of administered buprenorphine is elimi-
Fig 1. Plasma concentration–time profiles of buprenorphine (BN) and nor-BN (NBN) after intravenous administration to rats.
Fig 2. Cumulative biliary excretion of buprenorphine (BN) and nor-BN (NBN) in recipient rats after intravenous administration of BN to donor rats.
nated in the faeces (Ohtani et al., 1994). The mean excretion ratio of buprenorphine-glucuronide and norbuprenorphineglucuronide in the bile after administration of buprenorphine 0.6 mg/kg iv were approximately 75% and 19%, respectively, and that of unchanged buprenorphine and norbuprenorphine was only less than 1% (Ohtani et al., 1994) In contrast, the urinary excretion ratio of norbuprenorphineglucuronide was only 3.2% and that of buprenorphine and buprenorphine-glucuronide was less than 1% (Ohtani et al., 1994) The biliary and urinary excretion ratios of norbuprenorphine-glucuronide and unchanged norbuprenorphine after administration of norbuprenorphine were 85% and 0.1%, and 9.1% and 1.9%, respectively (Ohtani et al., 1994). The enterohepatic circulation of buprenorphine was confirmed in “linked-rat model” experiments. During a 24-h period, 25% of the dose given to the donor rats was found in the bile of the recipient rats as buprenorphineglucuronide, and 59% was found as norbuprenorphineglucuronide (Fig. 2) (Ohtani et al., 1994). The excretion ratio of norbuprenorphine-glucuronide was approximately twice that of buprenorphine-glucuronide. These results are markedly different from the results of the biliary excretion experiments in bile-fistula rats (Ohtani et al., 1994). Therefore, we consider that the difference in excretion pattern may result from the first-pass effects during enterohepatic circulation (Ohtani et al., 1994). Although the elimination of norbuprenorphine from the body was more rapid than that of buprenorphine, the mean plasma concentration of norbuprenorphine after 8-mg sublingual administration of buprenorphine was frequently equal to or higher than that of buprenorphine (Kulhman et al., 1998). This plasma concentration of norbuprenorphine was based on the increase in the proportion of norbuprenorphine-glucuronide observed after the enterohepatic circulation of buprenorphine due to first-pass metabolism. Pontani et al. (1985) discussed the reappearance of buprenorphine conjugates in the bile and hypothesized that buprenorphine conjugates undergo hydrosis, probably via the action of gastrointestinal microorganisms. We also found in our preliminary study that
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nearly 100% of buprenorphine and norbuprenorphine was liberated from the bile within 5 h when a bile sample containing conjugated buprenorphine was incubated with β-glucuronidase at 37°C (Ohtani et al., 1993) From these findings, it appears that buprenorphine-glucuronide and norbuprenorphine-glucuronide excreted in the bile may be absorbed after the return of the parent drugs, buprenorphine and norbuprenorphine, to the intestinal tract. Due to the extensive first-pass effect in the gut lining and liver, the systemic bioavailability of buprenorphine in humans following oral administration is approximately 10% (Robinson et al., 1992). 2.3. Metabolism Two metabolic pathways are well documented, that is, N-dealkylation by CYP3A4 and glucuronidation, leading to the three major metabolites of buprenorphine: buprenorphine-3-glucuronide; N-dealkylbupurenorphine, which is its only active metabolite; and norbuprenorphine-3glucuronide. The in vitro metabolic rate of glucuronidation and N-dealkylation of the 9000-g supernatant fraction in the liver and small intestine are shown in Table 1. There was no significant difference between the mean glucuronidation rate of buprenorphine and norbuprenorphine in the liver and small intestine. On the other hand, the N-dealkylation reaction was 100-fold greater in the liver than in the small intestine (Ohtani et al., 1993). The contents of cytochrome P-450 after repeated administration of doses of 0.03 to 0.6 mg/kg decreased significantly as compared with those in control rats given saline (Ohtani et al., 1994). On the other hand, there was no decrease with the 0.003 mg/kg dose as compared with control rats (Fig. 3) (Ohtani et al., 1994). This reduction in the contents of cytochrome P-450 is due to the cyclopropylmethyl group in the buprenorphine structure. The oxidation rate of buprenorphine in the liver in rats pretreated with buprenorphine 0.6 mg/kg was decreased to 20% of that in controls (Ohtani et al., 1994). In contrast, there was no decrease after the administration of 0.003 mg/kg as compared with the saline controls. There was no change in AST and ALT activities in the plasma at any dose in pretreated rats (Ohtani et al., 1993). Therefore, the most commonly used dosage for the treatment of pain has little effect on the oxidation rate. In vitro studies with human liver microsomes found
Table 1 In vitro metabolic rate for glucuronidation of buprenorphine (BN) and norbuprenorphine (NBN) and N -dealkylation for BN (values in ng/g/min) Tissue
Liver Small intestine
Glucuronidation
N -dealkylation
BN
NBN
BN
706 ± 122 572 ± 147
1340 ± 335 1635 ± 158
525 ± 175 6±0
Each value represents the mean ± SD of tree thrials.
Fig 3. Change in hepatic cytochrome P-450 contents during repeated dosing with buprenorphine.
that buprenorphine is a strong inhibitor of CYP3A4 and CYP2D6, and it also weakly inhibited CYP1A2, CYP2B6, CYP2C19, CYP2C8, CYP2C9, CYP2E1, and CYP2A6 (Ohtani et al., 1993). However, at the therapeutic concentration of buprenorphine, it would not be expected to cause clinically significant interactions with other drugs metabolized by CYP (Umehara et al., 2002).
3. Pharmacology 3.1. Analgesic effects Buprenorphine has a bell-shaped dose-response curve for antinociception and catalepsy (Zhang et al., 2003). However, the study by Zhang et al.(2003) was performed using high doses of buprenorphine, and the normal therapeutic dose range does not result in a bell-shaped dose-response curve. Instead, buprenorphine has been observed to exhibit a linear dose-response relationship in terms of analgesic effects. We compared the analgesic effects of buprenorphine and norbuprenorphine based on a pharmacokineticpharmacodynamic model (Ohtani et al., 1995). The change in latency time after intraventricular administration of buprenorphine or norbuprenorphine to rats is shown Fig. 4. After intraventricular injection of norbuprenorphine, the intrinsic analgesic activity was approximately 25% more potent than that of buprenorphine (Ohtani et al., 1995). The analgesic effects of norbuprenorphine after intravenous administration were approximately 2% of that of buprenorphine (Ohtani et al., 1995). To compare the lipophilicity between buprenorphine and norbuprenorphine, the n-octanol/ water partition coefficient of norbuprenorphine was 10% of that of buprenorphine (Ohtani et al., 1995). The brainto-plasma ratio of buprenorphine ranged from 1.1 to 3.3 (Ohtani et al., 1995). In contrast, the brain distribution of norbuprenorphine after administration was greatly reduced when compared with that of buprenorphine, and the brain-to-plasma ratio of norbuprenorphine was less than 0.1
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Fig 4. Change in latency time after intraventriclar injection of buprenorphine (BN) or nor-BN (NBN) to rats.
(Ohtani et al., 1995). Therefore, the weak analgesic effects of norbuprenorphine after intravenous administration may be due not only to the low permeability of norbuprenorphine into the brain, consistent with its low n-octanol/water partition coefficient, but also to its intrinsically weak analgesic effects. Therefore, the plasma concentration of norbuprenorphine with chronic administration of buprenorphine has little analgesic effect. Buprenorphine produces analgesic effects at a low plasma concentration. In contrast, norbuprenorphine does not produce analgesic effects within the therapeutic range. Therefore, the plasma concentration of norbuprenorphine with chronic administration of buprenorphine has little analgesic effect (Broude et al., 1974).
of 0.008 to 3 mg/kg (Ohtani et al., 1997). In contrast, the respiratory rate after an intravenous bolus administration of norbuprenorphine decreased in a dose-dependent fashion within the dose range of 1 to 3 mg/kg (Ohtani et al., 1997). The minimum respiratory rate was observed 15 min after norbuprenorphine administration (Ohtani et al., 1997). As shown in Fig. 5, the reduction in respiratory rate and the increase in pCO2 after buprenorphine administration was observed only with a high infusion rate. In contrast, norbuprenorphine decreased the respiratory rate and increased pCO2 dose dependently (Ohtani et al., 1997). The depression of the respiratory rate by norbuprenorphine was approximately 10-fold greater than that by buprenorphine (Ohtani et al., 1997). The respiratory rate depression induced by norbuprenorphine was immediately recovered after administration of β-FNA, a selective opioid µ-receptor (Ohtani et al., 1997). However, the respiratory depression was not improved by a selective δ-receptor antagonist, ICI 174864 (Ohtani et al., 1997). Therefore, we suggest that the depression of respiratory function is mediated by the µ-receptor. As shown in Fig. 6, after buprenorphine administration, analgesic effects are produced at a low plasma buprenor-
3.2. Respiratory depression The most dangerous complication of opioid therapy is respiratory depression. The lowest incidence of respiratory depression was found with buprenorphine. Based on the results of recent clinical and animal studies, the lack of respiratory depression with buprenorphine has clear clinical advantages over other classic µ]-agonist opioids (Dahan et al., 2005). After intravenous bolus administration of buprenorphine, no effects were noted over the dose range
Fig 6. Relationships between plasma concentration of buprenorphine (BN) or nor-BN (NBN) and analgesic effects or respiratory depression.
Fig 5. Relationships between infusion rate of buprenorphine (BN) or nor-BN (NBN) and respiratory rate or arterial pCO2.
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phine concentration, whereas respiratory depression is not induced even at a 1000-fold higher concentration. In contrast, to obtain analgesic effects with norbuprenorphine comparable to those with buprenorphine, it is necessary to maintain the norbuprenorphine concentration at a 50-fold higher value, at which point the concentration that induces respiratory depression is close to that producing analgesic effects (Ohtani et al., 1997). However, it is possible that the plasma level of norbuprenorphine observed with chronic administration of buprenorphine is not sufficiently high to cause depression of the respiratory rate (Ohtani et al., 1995). Recently, Dahan et al.(2005a) have shown that the ceiling for the respiratory effect occurs at a much lower dose than the ceiling for analgesic effects, which indicates the relative safety of buprenorphine combined with its ability to produce effective analgesia. Buprenorphine has a high affinity for and slow dissociation from µ-opioid receptors. Because of this, a single bolus administration of naloxone leads to partial, short-lived reversal of buprenorphineinduced respiratory (Dahan et al., 2005a). Thus, reversal of buprenorphine-induced respiratory depression requires a continuous infusion of naloxone (Dorp et al., 2006).
4. Conclusion In conclusion, the tissue distribution of norbuprenorphine has been shown to be less than that of buprenorphine, and the elimination of norbuprenorphine is more rapid than that of the parent drug. Buprenorphine and norbuprenorphine undergo extensive enterohepatic circulation. The plasma level of norbuprenorphine with chronic administration of buprenorphine was based on the increase in the proportion of norbuprenorphine-glucuronide observed after the enterohepatic circulation of buprenorphine due to first-pass metabolism. The amount of cytochrome P-450 and the oxidation rate of buprenorphine in the hepatic microsome fraction after repeated administration of doses ranging from 0.03 to 0.6 mg/kg decreased significantly as compared with those in control rats given saline (Ohtani et al., 1994). In contrast, there was no decrease after the administration of 0.003 mg/kg as compared with the saline controls (Ohtani et al., 1993). Therefore, the most commonly used dosage for the treatment of pain has little effect on the oxidation rate. The analgesic effects of buprenorphine are produced at a low plasma concentration, whereas respiratory depression is not induced even at a 1000-fold higher concentration. In contrast, the plasma concentration of norbuprenorphine with chronic administration of buprenorphine has little analgesic effect and respiratory depression. Overall, buprenorphine displays more favorable analgesic and respiratory pharmacology compared with other
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classic µ-agonists, and it is safe and highly effective in the treatment of pain. In particular, the transdermal patch formulation of buprenorphine is user-friendly, and patient compliance has been shown to increase and the quality of life of patients to improve with its use (Bohme., 2002). To ensure that buprenorphine preparations are used appropriately, it is necessary to enlighten clinicians who prescribe them for the treatment of pain.
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