Interplay of biopharmaceutics, biopharmaceutics drug disposition and salivary excretion classification systems

Abstract

The aim of this commentary is to investigate the interplay of Biopharmaceutics Classification System (BCS), Biopharmaceutics Drug Disposition Classification System (BDDCS) and Salivary Excretion Classification System (SECS). BCS first classified drugs based on permeability and solubility for the purpose of predicting oral drug absorption. Then BDDCS linked permeability with hepatic metabolism and classified drugs based on metabolism and solubility for the purpose of predicting oral drug disposition. On the other hand, SECS classified drugs based on permeability and protein binding for the purpose of predicting the salivary excretion of drugs. The role of metabolism, rather than permeability, on salivary excretion is investigated and the results are not in agreement with BDDCS.

Conclusion

The proposed Salivary Excretion Classification System (SECS) can be used as a guide for drug salivary excretion based on permeability (not metabolism) and protein binding.

1. Theoretical background and interplay

Drug effective permeability is a major key factor in its transport across all body membranes such as membranes in the intestine, liver, blood capillaries, blood brain barrier and salivary mucosa. An interesting finding was noted that when drug effective permeability is high in the intestinal mucosa, it will undergo high metabolism in the liver (Wu and Benet, 2005). Similarly, when drug effective permeability is high in the intestinal mucosa, it will undergo salivary excretion in the salivary mucosa (Idkaidek and Arafat, 2012).

BCS first classified drugs based on permeability and solubility for the purpose of predicting oral drug absorption as shown in Table 1. (Amidon et al., 1995), where high intestinal permeability corresponds to fractional absorption Fa > 0.9 and high solubility corresponds to the highest oral dose being soluble in 250 ml water. Then BDDCS linked permeability with hepatic metabolism and classified drugs based on metabolism and solubility for the purpose of predicting oral drug disposition as shown in Table 2 (Wu and Benet, 2005). BDDCS uses liver metabolism instead of permeability, since drug metabolism data are more available and consistent than permeability data, where high metabolism drugs have extraction ratios >70% and low metabolism drugs have extraction ratios <30%. It was found that 27 out of 29 high permeability drugs (93.1%) were highly metabolized in the liver, with few unexplained exceptions (Benet et al., 2008).

Table 1.

Biopharmaceutics Classification System (BCS) according to drug permeability (P_eff) and solubility (C_s).

Class	Parameter
	Peff	Cs
Class I	High	High
Class II	High	Low
Class III	Low	High
Class IV	Low	Low

Table 2.

Biopharmaceutics Drug Disposition Classification System (BDDCS) according to drug metabolism and solubility (C_s).

Class	Parameter
	Metabolism	Cs
Class I	High	High
Class II	High	Low
Class III	Low	High
Class IV	Low	Low

On the other hand, SECS classified drugs based on permeability and protein binding for the purpose of predicting the salivary excretion of drugs as shown in Table 3. (Idkaidek and Arafat, 2012). Similar to Biopharmaceutics Classification System BCS, Salivary Excretion Classification System (SECS) high intestinal permeability that corresponds to fraction absorption Fa > 0.9. On the other hand, high protein binding corresponds to low fraction unbound fu of <0.1 (Idkaidek and Arafat, 2012).

Table 3.

Salivary Excretion Classification System (SECS) according to drug permeability (P_eff) and fraction unbound to plasma proteins (fu).

Class	Parameter
	Peff	Fu	Salivary excretion
Class I	High	High	Yes
Class II	Low	High	Yes
Class III	High	Low	Yes
Class IV	Low	Low	No

The role of metabolism, rather than permeability, on salivary excretion is investigated and the results are not in agreement with BDDCS. It was found that only 10 out of 20 (50%) high permeability drugs were highly metabolized in the liver as shown in Table 4.

Table 4.

SECS, BCS and BDDCS interplay.

Drug	fu	Peff × 10−4 (cm/s)	Fa	Liver metabolisma	SECS class
Azithromycin	0.71 (H)	29.74	1.00 (H)	E	I
Sitagliptin	0.62 (H)	13.75	1.00 (H)	P	I
Tolterodine	0.37 (H)	10.74	0.99 (H)	E	I
Carbamazepine	0.24 (H)	20.0	1.00 (H)	E	I
Erythromycin	0.31 (H)	36.68	1.00 (H)	E	I
Fluconazole	0.89 (H)	13.15	1.00 (H)	P	I
Norfloxacin	0.68 (H)	10.85	0.99 (H)	P/E	I
Paracetamol	0.99 (H)	74.33	1.00 (H)	E	I
Metformin	0.99 (H)	1.44	0.83 (L)	P	II
HCT	0.33 (H)	0.16	0.18 (L)	P	II
Cinacalcet	0.03 (L)	44.16	1.00 (H)	E	III
Cloxacillin	0.05 (L)	10.04	0.99 (H)	P	III
Rosuvastatin	0.1 (L)	32.15	1.00 (H)	P	III
Phenytoin	0.1 (L)	10.51	0.99 (H)	E	III
Tamsulosin	0.01 (L)	0.71	0.58 (L)	E	IV
Montelukast	0.01 (L)	1.13	0.75 (L)	E	IV
Lornoxicam	0.1 (L)	0.39	0.38 (L)	E	IV
Losartan	0.01 (L)	1.11	0.75 (L)	E	IV
Diacerhein	0.01 (L)	0.84	0.65 (L)	E	IV
Ibuprofen	0.01 (L)	1.35	0.81 (L)	E	IV

^aE: extensively metabolized (>70%); P: poorly metabolized (<30%), as obtained from Ref. Custodio et al. (2008) or drug monographs.

2. Conclusion

From the regulatory point of view, the US FDA guidance for industry stated that “The statutory definitions of BA and BE, expressed in terms of rate and extent of absorption of the active ingredient or moiety to the site of action, emphasize the use of pharmacokinetic measures in an accessible biological matrix such as blood, plasma, and/or serum to indicate release of the drug substance from the drug product into the systemic circulation” (Guidance for industry: bioavailability and bioequivalence studies for orally administered drug products – general considerations, 2003). Hence, the proposed Salivary Excretion Classification System (SECS) can be used as a guide for drug salivary excretion based on permeability (not metabolism) and protein binding.